Like many others
from more Northern climes, a retired man from upstate
New York migrates to Florida for the winter (a
“snowbird”). Due to high cholesterol and certain other
detected elevated cardiovascular risk factors, he is
prescribed a statin,
(Lipitor). In addition, he adopts a modified lifestyle
that includes improved exercise and diet, including
generous amounts of fresh citrus, as part of which he
elects to consume two or three glasses of fresh
grapefruit juice daily. He begins experiencing muscle
pain, fatigue and fever, and requires emergency room
treatment, where he goes into renal failure and dies,
all within the space of 2 months from migration. The
fatality, described in detail by Amy Karch, R.N.273,
was consequent to co-consumption of grapefruit juice, a
known CYP3A4 inhibitor, with atorvastatin, a statin
metabolized by CYP3A4 – as are also an estimated over
4000 other prescription medications.
As the label drug
interactions warns, concomitant administration of
atorvastatin with strong CYP3A4 inhibitors can lead to
increases in plasma concentrations of atorvastatin. And
the label does carry an explicit warning about
grapefruit juice co-consumption but it suggests that
adverse interaction is largely secondary to high
grapefruit juice consumption, of the order of 1.2 liters
(~5 glasses); this is misleading: as in the Karch case,
as little as 2 – 3 glasses, and possibly even a single
glass (from sporadic case reports), can prove fatal
under wide variability of pharmacokinetic parameters.
That was shown in another case from the burgeoning arena
that has sometimes come to be known as “death by citrus”
which includes the fatality of a 29-year old healthy man
who consumed just two glasses of grapefruit juice while
taking terfenadine (Seldane) antihistamine medication
(since 1998, removed from market), inducing fatal
cardiac arrhythmias via prolongation in the QT interval,
secondary to CYP3A4-mediated ultra-toxic levels of
Regrettably, as in so many cases of adverse
pharmacokinetics, no heed was paid to the drug
interaction label warning (which we would argue could be
less circumspect, and raising the warning to a
contraindication, it strikes us, may be more prudent).
highlights the importance of drug-drug, drug-herb,
drug-nutraceutical, and drug-food interactions,
collectively referred to as DDI (Drug-Drug Interactions)
in the expanded sense of “drug” as inclusive of
pharmaceutical as well as natural and dietary food
agents. As will be seen below, we also have the opposite
phenomenon, not of increased serum concentrations, but
of clinically significant reduction of drug
concentration, as from the case of coadministration of
tamoxifen, a CYP2D6-mediated agent, with
CYP2D6-inhibitory agents such as certain SSRIs or the GI
agent cimetidine (Tagamet), among many others, leading
to a decidedly adverse impact on a survival endpoint,
inducing a significantly worse time to recurrence (TTR)
and disease free survival (DFS) in breast cancer
Similarly, as we
document extensively below, drug-food interactions can
be of clinical significance: garlic decreases the levels
of antiretroviral (ARV) / protease inhibitor drugs
including saquinavir (Invirase) and ritonavir (Norvir),
and a seminal garlic–saquinavir interaction study274
found a 51% decrease in saquinavir oral bioavailability
consequent to garlic-induced CYP3A4 induction, from as
little as two cloves (4 g/each) of garlic.
Clinician’s Dilemma (and A Solution)
However, it will
also be shown below that (1) many preclinical signals
raised re potential adverse interactions either may not
be of consequence looking at higher human clinical data,
and hence lacking in clinical relevance, or that (2) it
should not be assumed that such potential adverse
interactions necessitate a wholesale prohibition against
concurrent administration. Consider the case of
resveratrol where preclinical data102
found that it may strongly diminish the susceptibility
of MDA-MB-231 cells triple negative breast cancer cells
to paclitaxel-induced apoptosis in vitro, and also in
vivo. Given that, there are also potential benefits of
resveratrol in the oncology context: thus, a recent
small randomized controlled double-blind trial275
of the effects of trans-resveratrol in women at
increased breast cancer risk observed a decrease in
methylation of the tumor suppressor gene RASSF-1α. And
we note further that another RCT conducted at the
University of Leicester found that micronized
resveratrol, compared with tissue from the
placebo-treated patients, in patients with hepatic
metastases significantly increased in malignant hepatic
tissue cleaved caspase-3 by 39%, which is known to be a
marker of apoptosis. Albeit preliminary these randomized
human clinical data suggest clinically relevant
potential benefits. However the potential for adverse
diminution of paclitaxel-induced apoptosis remains as we
We would argue,
with that caution in mind, that in fact it is feasible
to accommodate synchronous but not simultaneous use of
resveratrol and paclitaxel: the half-life of paclitaxel
(Taxol) is short, at 5.6 hours, so separating
resveratrol consumption by 24 hours on either side of
paclitaxel administration evades the problem, given that
the half-life of resveratrol itself is only ~9 hours.
This strategy, which we have often deployed in clinical
context, is a “window of safety” approach that allows
synchronous administration without true simultaneous
use, enabling potential benefits without triggering
significant harms, and in fact uses pharmacokinetics to
resolve a problem itself raised by pharmacokinetics.
in other contexts may be shift of agent within the same
class of drugs as that of some problematic agent.
Consider the case of statins: atorvastatin
(Lipitor), among several other statins, is a known
CYP3A4-inhibitor, entailing significant potential for
adverse interaction with other CYP3A4-mediated agents
such as the aromatase inhibitor (AI) exemestane
(Aromasin). But if comparable lipid control can be
obtained, then pravastatin (Pravachol) – or simvastatin
(Zocor) or rosuvastatin (Crestor) if needed - can be
used in place of atorvastatin (Lipitor), as these
are all statins without significant p450-mediated
strategy could be deployed with benzodiazepines most of
which exhibit strong CYP3A4 (and some other) metabolic
dependencies: in the real-world context, this would
suggest substituting lorazepam for the CYP3A4-mediated
diazepam, since lorazepam is devoid of clinically
significant CYP hepatic enzyme dependencies.
molecular mechanisms underlying drug interactions
include efflux pump proteins in the ATP-binding cassette
(ABC) transporter superfamily, most notably the ABC
proteins like P-glycoprotein (P-gp; ABCB1), the vast
majority of potential adverse interactions stem from the
cytochrome P450 (CYP) family of hepatic enzymes,
especially CYP3A4 (over 50% of prescription drugs277,
~7000+), along with in particular the CYP 1A2, 2B6, 2C9,
2C19, and 2D6 enzyme subfamilies, and the cytochrome
P450 enzyme family is therefore our focus below.
Inhibitors | Inducers Substrates
In the world of
Cytochrome P450 system
is a CYP enzyme (technically,
that simply performs a reaction on a medication, an
inhibitor is an agent binding so strongly to a
that it prevents the enzyme from metabolizing other
medications, while an inducer is an agent that interacts
with the enzyme to cause new production of the enzyme.
Thus, an inhibitor of a specific CYP isozyme may
decrease the metabolism of the drug and hence increase
serum concentrations - and toxicity - of drugs that are
substrates for that isoenzyme, while an inducer of a
specific CYP isozyme may increase the metabolism of the
drug and decrease serum concentrations - and efficacy -
of drugs that are substrates for that isozyme.
Anthracyclines and taxanes, as well as the aromatase
inhibitor exemestane (Aromasin) and the vinca alkaloid
vinorelbine (Navelbine) are predominantly metabolized by
the CYP3A4 enzyme, and so we say they are
CYP3A4-mediated. And many other agents are either
CYP3A4-inducers and CYP3A4-inhibitors. An
will increase the concentration of another agent it's
given with (because it inhibits its clearance, and so
allows the agent to remain in the system longer than
required, increasing toxicity), while an
will decrease the concentration of another agent it's
given with (because it enhances its clearance, and so
allows the agent to remain in the system less time than
required, decreasing efficacy). Grapefruit juice is a
CYP3A4-inhibitor, and so if consumed with most
chemotherapies, will dangerously increase the toxicity
of the chemotherapy agent, with hazardous adverse
effects and morbidities, and some documented fatalities.
agents are CYP3A4 inducers or inhibitors and therefore,
like grapefruit juice, can either increase the toxicity,
or reduce the efficacy, of several chemotherapy agents I
noted above, and of the AI exemestane (Aromasin), and
these include St. John's Wort, goldenseal, chamomile,
sage and licorice teas, and the oils of Evening Primrose
and Borage, among others, and so it is prudent to avoid
co-consumption during oncotherapy with the agents I
noted which are CYP3A4-mediated in their metabolism.
Certain statins can also interfere with these same
chemotherapy agents, and with the aromatase inhibitor
(AI) exemestane (Aromasin).
of adverse interaction concerns tamoxifen metabolism:
tamoxifen is predominantly CYP2D6-mediated, and St.
John's Wort and all SSRI type antidepressants can
interact across the CYP2D6-mediated enzyme to render
tamoxifen to near-placebo levels, with obvious and dire
consequences, and the clinical relevance, not just in
vitro and in vivo, of this was been well established.
lesson is that extreme caution needs to be exercised to
assure that coadministration of agents jointly
metabolized across the same cytochrome p450 system
enzyme not induce adverse interactions. Avoiding
inadvertent compromise of the efficacy and/or safety of
the broad spectrum of oncotherapies requires
considerable care, and there is therefore unfortunately
bound to be a large body of patients whose oncotherapy
efficacy may have been compromised not by being
refractory to it, or resistant, but rather by
then-unknown adverse agent interactions.
-- Issues in
Tamoxifen is converted into its active metabolites
and other active metabolites, in the liver by the
liver enzyme, one of many CYP enzymes that are part of
the liver's P450 detoxification pathway (aka the hepatic
cytochrome P450 enzyme
and primarily responsible for the metabolism of
tamoxifen into its active metabolites (plasma
concentrations of these active metabolites are
associated with the cytochrome P450 (CYP) 2D6 genotype).
We now know that the efficacy of tamoxifen therapy for
the treatment of breast cancer exhibits wide individual
variation that appears to be genetic, with some women
able to convert tamoxifen into active metabolites more
effectively than others; women with the normal gene
produce somewhere in the order of two to four times as
much of active metabolites as those with the variant
that is a relatively ineffective tamoxifen active
and SSRI Antidepressants
Working from the fact that
SSRI ( selective
serotonin reuptake inhibitor)
are known to be CYP2D6 enzyme inhibitors, Stearns and
identified a previously unrecognized active metabolite
and found that endoxifen was present in substantially
higher concentrations than 4-hydroxy-tamoxifen, but
after administration of the SSRI antidepressant
treatment, endoxifen levels decreased, but levels of
4-hydroxy-tamoxifen did not. At that time, the
researchers suggested that CYP2D6 genotype and drug
interactions should be considered in women treated with
tamoxifen; however, the precise clinical implications of
low circulating endoxifen concentrations were not fully2.
Some of the same researchers3
have revisited this problem, reporting preliminary data
from an ongoing prospective study to confirm the
original findings. The later study found that certain
CYP 2D6 genotypes, as well as the use of the CYP 2D6
inhibitor SSRI antidepressants sertraline and paroxetine
strongly influence tamoxifen conversion to endoxifen.
However we note that although endoxifen levels were
affected adversely, there was no change in
concentrations of tamoxifen itself or its other
metabolites, thus still leaving unclear the clinical
implications of these results (the authors concluded
that therefore the findings are still insufficiently
powered to dictate any change to prescribing practices
at that time).
We further note
that although the SSRIs
as CYP2D6 inhibitors were associated with low
concentrations of endoxifen, the dual mechanism agent
a serotonin/norepinephrine reuptake inhibitor (SNRI),
was not, suggesting that the SNRI venlafaxine (Effexor)
in particular may be a potential workaround for breast
cancer patients requiring hot flash relief (although we
note that gabapentin is also an effective alternative
choice; see below our discussion of neuroactive agents).
Some confirming evidence of this advantage for
venlafaxine was recently put forward by Jin et al. in
their prospective observational study4
which found that plasma endoxifen concentration was only
slightly decreased by venlafaxine, a weak inhibitor of
CYP2D6, but substantially reduced in subjects who took
paroxetine (Paxil), a potent inhibitor of CYP2D6), with
again the magnitude of the reduction in plasma endoxifen
concentration associated with CYP2D6 inhibitor use
dependent on the CYP2D6 genotype. The researchers
however prudently note that although SSRIs may affect
tamoxifen’s antitumoral efficacy or its side effects,
this hypothesis requires further testing in actual
-- Tamoxifen and
Although therefore the SNRI
is a weak CYP2D6 inhibitor, the two other SNRIs
both appear to have significant potential interaction
across CYP2D6 and hence may raise similar adverse
review of the literature, as of April 2008, for
potentially adverse significant interactions between
tamoxifen CYP2D6 metabolism and any antidepressant
including SSRIs, SNRIs, tricyclics (TCAs), and various
atypicals such as
(Wellbutrin), nefazodone (Serzone), among others, has
failed to uncover decisive evidence of any wholly
unproblematic antidepressant outside of what is already
known solely on venlafaxine (Effexor), and the just
FDA-approved venlafaxine analog, desvenlafaxine
(Pristiq). However, there are some qualifications to be
(1) Mirtazapine (Remeron) at pharmacological
concentrations can moderately increase the activity of
CYP2D in hepatocytes, with the CYP2D2 isoform being the
principle contributor to this effect5,
and the available
vitro and in vivo data suggest that mirtazapine is
unlikely to affect the metabolism CYP2D6- metabolized
and this having been cross-confirmed and extended
to include improbable inhibition of CYP1A2 and CYP3A4
However, there are apparently some discordant findings
on CYP2D6: German researchers have found in a small
human study that the clearance of CYP2D6 intermediate
metabolizers was reduced by 26% compared with that of
extensive metabolizers, but we note that this magnitude
of decrement is unlikely to be appreciably above
borderline clinical significance8.
Finally, we should note that the official mirtazapine
(Remeron) labeling bares the following warning:
"In vitro studies have shown that mirtazapine is a
substrate for several of these enzymes, including 2D6,
1A2, and 3A4. While in vitro studies have shown that
mirtazapine is not a potent inhibitor of any of these
enzymes, an indication that mirtazapine is not likely to
have a clinically significant inhibitory effect on the
metabolism of other drugs that are substrates for these
cytochrome P450 enzymes, the concomitant use of REMERON®
with most other drugs metabolized by these enzymes has
not been formally studied. Consequently, it is not
possible to make any definitive statements about the
risks of coadministration of REMERON® with such drugs."
which we note is in agreement with the conclusions
stated by Leon Delbressine and Ria Vos with Organon: "the
contribution of its [mirtazapine] metabolites to the
pharmacologic effect is negligible";
has no inducing or inhibiting effects on the hepatic
has a very low potential for clinically relevant
pharmacokinetic interactions with other drugs; and its
disposition is independent of polymorphic CYP2D6
(2) As for the
atypical antidepressant bupropion (Wellbutrin), in vitro
research has shown that it is primarily metabolized to
its major metabolite hydroxybupropion by the CYP2B6
and this suggests caution in coadministration with
CYP2B6 substrates such as cyclophosphamide (Cytoxan)
which is both a CYP2B6 and CYP2C19 substrate11
and accordingly bupropion (Wellbutrin) bares a label
warning to this effect, with some caution required also
if coadministered with promethazine (Phenergan), among
many other CYP2B6 substrates.
And although we
note that this is the only CYP enzyme (CYP2B6) noted as
a label warning, it appears that there may also be some
significant CYP2D6-mediated interactions12,13.
On the one hand,
labeling indicates that CYP2D6 is inhibited by bupropion
or hydroxybupropion, and on the other the study of Leah
Hesse at Tufts and her colleagues14
suggests that at the in vitro level bupropion and
hydroxybupropion have relatively low CYP2D6 inhibitory
potential, concluding that "bupropion
does not inhibit CYP2D6 in vivo and that bupropion
itself is not likely to be a substrate for CYP2D6",
while on the other we have human volunteer studies such
as that of Michael Kotlyar and colleagues (see above)
which has suggested a greater potency, at a level of
clinically significant adverse interactions and whose
study concluded that "Bupropion
is therefore a potent inhibitor of CYP2D6 activity, and
care should be exercised when initiating or
discontinuing bupropion use in patients taking drugs
metabolized by CYP2D6".
Nonetheless, despite these dissonant findings, the
balance of the evidence suggests that bupropion inhibits
CYP2D6 and hence may reduce clearance of
CYP2D6-metabolized agents, and we consider recent
studies as confirmatory of this conclusion, including
James Jefferson at the University of Wisconsin and
and the recent findings of the GSK team of Melissa Reese
who concluded that the "reductive
metabolites of bupropion are potent competitive CYP2D6
inhibitors in vivo",
and coupled with the human clinical cases cited above,
the CYP2D6-inhibitory activity of bupropion (Wellbutrin,
Zyban) should be assumed to carry at least a non-trivial
potential for significant adverse interactions in humans
when coadministered CYP2D6-metabolized agents.
Other Issues re Tamoxifen Pharmacokinetics
More recently still Hiltrud Brauch and colleagues17 with the
German AGO TRAFO Commission further confirmed that
recent mechanistic, pharmacologic, and clinical
pharmacogenetic evidence suggests that genetic variants
and drug interaction by CYP2D6 inhibitors, with CYP2D6
being the key enzyme in tamoxifen biotransformation into
the clinically relevant metabolites, 4-OH-tamoxifen and
endoxifen, influence plasma concentrations of active
tamoxifen metabolites and consequently outcome of the
patients treated with adjuvant tamoxifen, with
non-functional (poor metabolizer) and severely impaired
(intermediate metabolizer) CYP2D6 variants being
associated with higher recurrence rates. This suggests
(1) that strong CYP2D6 inhibitors such as SSRI
antidepressants should be avoided as co-medication, and
(2) that there is an important role for pre-treatment
CYP2D6 genotyping to predict metabolizer status and
hence outcome, enabling individualization of endocrine
treatment choice and benefit.
In addition, as
we note elsewhere in this review, although tamoxifen
metabolism is primarily CYP2D6-mediated,
there is still a partial non-trivial CYP3A4 dependency.
In this connection, William Chi at Princess Margaret
Hospital and colleagues18
have found that a genetic variant of the CYP3A4 gene,
CYP3A4*1B, influences endometrial cancer risk: women
carrying the CYP3A4*1B allele had 3-fold increase in the
risk of developing endometrial cancer from tamoxifen
treatment compared with women not on tamoxifen,
suggesting that a subgroup of breast cancer patients -
namely, CYP3A4*1B allele carriers on tamoxifen - may be
at increased risk of developing endometrial cancer.
Aromatase Inhibitors (AIs)
As to the aromatase inhibitors (AIs), there is the
potential for drug-drug or drug-herb interactions for
all three aromatase inhibitors (AIs), but to
significantly different degrees, if there is concomitant
medication that interacts with certain cytochrome P450
Anastrozole (Arimidex) inhibits (in decreasing order of
magnitude) CYP1A2, CYP2C8/9, and CYP3A4 (as noted by
AstraZenica scientists Scott Grimm and Martin Dryoff19.
However, although anastrozole (Arimidex) metabolism is
in part CYP1A2, CYP2C8/9, and CYP3A4-mediated, and
carries an FDA labeling warning to that effect, the FDA
has concluded - in the same warning - that these
dependencies exist but only at relatively high
concentrations in vitro and therefore that it is
unlikely that co-administration of a 1-mg dose of
Arimidex with other drugs would result in clinically
significant drug inhibition in vivo, and as per
AstraZenica scientists Scott Grimm and Martin Dyroff's
determination, cited above), anastrozole (Arimidex)
would not be expected to cause clinically significant
interactions with other CYP-metabolized drugs at
physiologically relevant concentrations achieved during
oncotherapy with anastrozole (Arimidex); we have
determined that this is further confirmed by Masha Lam
and Robert Ignoffo in their review20.
However, there is known drug-drug interaction of
tamoxifen with anastrozole21
(and with letrozole, see below): concomitant
administration of either anastrozole or letrozole with
tamoxifen decreases the plasma level of the AI.
Anastrozole and tamoxifen administrated concomitantly in
the ATAC trial lowered the plasma anastrozole level in
the combined arm by 27%.
(Femara) strongly inhibits CYP2A6, moderately inhibits
CYP2C19, and has a low affinity for CYP3A4. This low
affinity for CYP3A4 suggests minimal potential for
adverse interactions across this enzyme. However,
there is a suspicion from the Royal Marsden team that
there may be some not wholly resolved or understood
adverse pharmacokinetics across CYP2D6 since Mitch
Dowsett and colleagues have decisively demonstrated that concomitant administration of letrozole and tamoxifen
decreased the level (plasma AUC) of letrozole by 38%22 and given that we know there is only weak affinity of letrozole with CYP3A4, wholly insufficient to explain such a dramatic reduction in letrozole levels (38%), and given that tamoxifen is otherwise only mediated significantly by CYP2D6, the Royal Marsden results raise a caution that some adverse - and clinically significant - interaction across CYP2D6 may yet be activated in a CYP2D6-mediated fashion.
So it should be noted with respect to strong CYP2A6 -
and possibly a suspicion also of CYP2D6 -
inhibition and moderate CYP2C19 inhibition, in addition
to being a CYP3A4 substrate, letrozole (Femara)
bares an FDA label warning to that effect (see also23,24).
(Aromasin) is metabolized by CYP3A425.
And although no drug-drug interactions have been
formally reported for exemestane (Aromasin), there
remains the potential for interactions with drugs,
nutritional agents and herbals that affect CYP3A4.
The antiestrogen fulvestrant (Faslodex) has no
clinically significant p450 enzyme-mediated
Learned re Endocrine Agents
cancer patients undergoing therapy with the following
require cautions as indicated:
Note that the paclitaxel-based taxanes - paclitaxel
(Taxol) and nab-paclitaxel (Abraxane) - exhibit
first-pass extraction by cytochrome P450-dependent
metabolic processes, with the CYP2C8 isoenzymes
metabolizing paclitaxel to the major metabolite
6-hydroxypaclitaxel the M5 metabolite), and CYP3A4
metabolizing paclitaxel to 3-hydroxypaclitaxel, a
minor metabolite (the M4 metabolite)26,27,28.
(vinorelbine (Navelbine), vinblastine (Velban),
(mainly CYP2D6-mediated, but potential
CYP3A-mediation in addition).
biological anti-VEGF / antiangiogenic agent
undergoes complex biotransformation by different
enzymatic routes which includes CYP3A429
(which is reversibly inhibited by bevacizumab
(Avastin) and other monoclonal antibodies (MoAbs)).
is a substrate of CYP3A4, CYP3A5 and CYP2D1930.
Since lapatinib (Tykerb) is extensively metabolized
by cytochrome P450 isoenzyme CYP3A4, concomitant use
of strong CYP3A4 inhibitors (including grapefruit
juice) can increase lapatinib plasma concentrations
and may induced untoward toxicity. If it is
necessary to coadminister a strong CYP3A4 inhibitor,
pharmacokinetic study data suggest that a dosage
reduction to 500 mg/day of lapatinib may adjust AUC
(area under the curve) to an appropriate range, and
it should be noted that if a strong CYP3A4 inhibitor
is discontinued, the FDA advises a washout period of
approximately 1 week prior to adjusting the
lapatinib dose upwards. In contrast, concomitant use
of strong a CYP3A4 inducer (like dexamethasone,
carbamazepine, or St. John's Wort, among many
others) should be avoided because of the consequent
decrease in lapatinib plasma levels. In this case,
if coadministration of a strong CYP3A4 inducer is
required, lapatinib dosing should be gradually
titrated from 1250 to 4500 mg/day based on
tolerability, with normal dosing of lapatinib
resumed after discontinuation of the CYP3A4 inducer31,32.
should be cautioned to avoid concurrent use of these
CYP3A4-mediated agents: (1) goldenseal and chamomile
extracts and teas, (2) St. John's Wort, (3) spices sage,
thyme and cloves, (4) soybean components daidzein and
genistein, (4) grapefruit juice (via its active
component pergamottin), and (5) licorice extracts and
teas (via its glabridin active component) to avoid
potential and significant modification of the antitumor
activity / efficacy, and/or toxicity, of these
chemotherapeutic agents; the evidence on potential
adverse pharmacokinetics via CYP3A4 with Serenoa repens
(Saw palmetto), and EPO (Evening Primrose Oil) / Borage
(seed) Oil remains equivocal.
Natural Agent Interactions
-- Black Cohosh
The black cohosh extracts can potentially (1) increase
the cytotoxicity of doxorubicin and docetaxel and (2)
decrease the cytotoxicity of cisplatin, radiation and
4-hydroperoxycyclophosphamide (4-HC), an analog of
In addition, black cohosh has been found to be a potent
CYP3A4 inhibitor in vitro34,
and this has some grave implications for cancer
therapies, given clinical risks associated with changes
in either the bioavailability or the metabolic rate of
clinically administered drugs. Over 50% of clinically
used drugs are oxidized by CYP3A4, which is part of the
family of cytochrome P450 (CYP) enzymes responsible for
drug metabolism, carcinogenesis (process by which normal
cells are transformed into cancer cells) and degradation
of xenobiotics (substances foreign to the biological
system). However in our critical appraisal of this study
we note that this study appears to have used an
excessively high dosage of 40 mg of the herbal extract
itself, not 40 mg of the herbal drug, the latter being
the standard formulation of the Remifemin black cohosh
product, and given this, the methodological legitimacy
of the conclusions of the widely-cited Tsukamato study
are undermined. Indeed, human clinical data has found
that black cohosh appears to have no clinically relevant
effect on CYP3A activity. The level of CYP3A4 inhibition
is estimated at approximately 44% with black cohosh),
adversely increasing the bioavailable concentration of
drugs metabolized by the CYP3A4 enzyme in the blood
(plasma concentrations) via the downregulation
suppression of CYP3A4. However, these are strictly in
vitro estimates and have been recently shown to be of no
clinical significance: Bill Gurley and his coresearchers35
who conducted a human clinical trial assessing the
effects of black cohosh (and milk thistle)
supplementation on CYP3A activity, finding that black
cohosh appears to have no clinically relevant effect on
CYP3A activity in vivo (true also of milk thistle). This
highlights the importance of at least in vivo
confirmation of preliminary in vitro data.
In sum: Concomitant
administration of certain dietary / nutritional
(including grapefruit, white pepper, and strawberry
fruit/Schisandra) and herbal agents is known to affect
drug metabolism in humans via inhibiting CYP3A4
activity. Chemotherapy agents that are known to be
metabolized by CYP3A4 include docetaxel (Taxotere),
paclitaxel (Taxol), etoposide (VePesid, Etopophos,
Toposar), irinotecan (Camptosar), ifosfamide (IFEX),
imatinib (Gleevec), vinorelbine (Navelbine), vinblastine
(Velban), and vincristine (Oncovin).
-- Other Herbals:
CYP2D6 and CYP3A4 Activity
Note that the popular herbal goldenseal is also a CYP3A4
and the same cautions should therefore apply; in
addition goldenseal is also, like SSRI antidepressants
and St. John's Wort, a CYP2D6 inhibitor and therefore
could potentially compromise the antitumor efficacy of
chemotherapeutic agents metabolized by this enzyme, the
most critical of which is tamoxifen, but also affects
the taxane docetaxel (Taxotere). St. John's Wort
increases cytochrome P450 3A (CYP3A) activity, but
docetaxel is inactivated by CYP3A (on docetaxel
so that the overall consequence seems to be that
subtherapeutic docetaxel concentrations may result when
docetaxel is administered to patients using St. John's
Wort on a chronic basis38.
Other CYP3A4 inhibitors include Chamomile extracts and
Serenoa repens (Saw palmetto)40,
as well as other herbals and spices such as sage, thyme, cloves, the soybean components daidzein and
pergamottin (active component of grapefruit juice) and
(active component of licorice extracts and teas).
As to the herbal
one recent study43
concluded that valerian was the only herb (of 6 studied)
that showed a mechanistic inhibition of CYP2D6 activity
and that this would therefore suggest caution as to a
potential toxicity but as this study was solely an in
vitro investigation, it strikes us that the judgment is
considerably ahead of the strength of the evidence. And
this is supported by the manifestly stronger human
clinical trial undertaken by Jennifer Donovan at the
Medical University of South Carolina and colleagues44
who found that valerian supplementation at 10.2 mg of
valerenic acids daily was associated with a modest
increase in alprazolam (Xanax) maximum concentration
(Cmax), so typical doses of valerian were unlikely to
produce clinically significant effects on the
disposition of medications dependent on the CYP2D6 or
CYP3A4 pathways of metabolism, and that furthermore the
magnitude of the Cmax increase - approximately 20% - was
unlikely to be of clinical significance, suggesting
therefore that valerian is unlikely to have clinically
relevant effects on the disposition of medications that
are primarily CYP2D6 or CYP3A4 metabolic pathway
dependent. [We note here that recent research45
has clarified that valerian may in fact exhibit
pronounced anxiolytic (anti-anxiety), and
antidepressant, activity rather than true sedative
activity]. Other agents such as silymarin
and ginseng, like curcumin, demonstrated no significant
CYP3A4 activity. On the other hand, kava kava, like
quercetin, and also grapeseed extract (GSE), proved
inductive of CYP3A4. Citrus aurantium (Bitter orange),
Panax ginseng, milk thistle (silymarin/silybin), and saw
palmetto extracts taken by healthy volunteers all had no
effect on the activity of CYP3A4, CYP1A2, CYP2E1, and
CYP3A4 measured using model substrates46,
but in contrast Echinacea exhibits significant effect47.
And still other herbal agents such as C aurantium, milk
thistle, or saw palmetto extracts appear to pose a
minimal risk for CYP-mediated herb-drug interactions in
note that we have here conflicting results for saw
palmetto (see Yale & Glulich, above) and it may be that
different components are involved, possibly also with
component-dose dependencies, much like those seen with
St. John's Wort. In addition, it has been demonstrated47
that interactions of Echinacea with anticancer drugs
that are substrates of CYP3A4 is likely.
-- St. John's
And note that St. John's Wort is not only a CYP2D6
inhibitor, but also a CYP3A4 inducer48,49
which may potentially result in lack of therapeutic
efficacy of taxanes and Vinca alkaloids, in contrast to
black cohosh which is a CYP3A4 inhibitor and so may
potentially result in increased bioavailability and
plasma concentration of these same drugs, where here the
concern would not be loss of therapeutic efficacy but
rather adverse increased toxicity. Note that the
pharmacokinetics of paclitaxel (Taxotere) is somewhat
different from that of docetaxel, undergoing significant
metabolism by the CYP2C8 enzyme50.
In addition, St. John's Wort has exhibited
pharmacokinetic interactions with irinotecan
(Camptosar), imatinib (Gleevec), as well as docetaxel
(Taxotere), as noted above.
However, we note that St. John's Wort
preparations not containing substantial amounts of
hyperforin (meaning, under 1%) have not been shown to
produce clinically relevant enzyme induction and
clinical studies using such low hyperforin preparations
have clearly demonstrated the superior antidepressant
efficacy over placebo, as well as its equivalence to
imipramine (Tofranil, Janimine) and fluoxetine (Prozac)
in the treatment of mild to moderate forms of
depression. In sum, it would appear that a
low-hyperforin preparation (and typically standardized
otherwise to 0.3% hypercin) would not exhibit adverse
chemotherapeutic interactions if hyperforin content were
assured to be less than 1%. On the other hand, the other
major component of St. John's Wort, hypercin, does not
appear to affect any of the p450 drug metabolizing
enzymes, including CYP2D6 and CYP3A452.
And these findings are borne out by a recent clinical
assessment and RCT53
which revealed significant induction of CYP3A4
(approximately 140%) by St. John's Wort.
Melatonin is known to enhance tamoxifen's antitumor
activity as evidenced both in preclinical studies and in
the seminal human clinical trials of Lissoni. This is
possible because SERMs exert their activity not directly
but through metabolites across distinct pathways
(tamoxifen's antitumor-activity metabolite is endoxifen
via the P450 CYP2D6 gene enzyme system, while
melatonin's biologically active metabolite is
6-hydroxymelatonin (6-OHMel); indeed it is known that
tamoxifen can modulate melatonin biotransformation over
the sulfotransferase (SULT) enzyme 1A1 pathway, thus
exerting additional antitumor activity. Finally,
remember that unlike tamoxifen, melatonin exhibits
multiple anti-estrogenic mechanisms besides SERM
The (Putative) "Dark Side", Corrected
Curcumin has been
found to inhibit platelet aggregation in vitro54,55,56,
and has been found to decrease the aggregation rate in
These findings suggests that curcumin may play the role
of a platelet aggregation inhibitor, functioning like
clopidogrel (Plavix) but not interfering with it, rather
reinforcing and enhancing its fundamental protective
activity, leading to the conclusion that "These
results clearly suggest that spice principles [including
curcumin] have beneficial effects in modulating human
leading to antithrombotic beneficial effects in
cardiovascular atherothrombotic diseases. Note that
omega-3 fatty acids (EPA/DHA) as well as EGCG may also
have contributory antiplatelet benefit. Therefore,
although we lack direct human clinical confirming data,
antiplatelet therapy such clopidogrel (Plavix) dosing
may need to be adjusted when there is co-consumption of
curcumin, EGCG, or omega-3 fatty acids during active
In addition, a
number of studies, most recently by Cao et al.59
appear to suggest that high-dose curcumin might induce
extensive mitochondrial DNA damage; however, whether
this is clinically significant overall is undetermined,
and the authors note that such damage might only be an
initial event triggering subsequent favorable
curcumin-induced apoptosis / cell death. Yet in the
aggregate, as Stig Bengmark of the Institute of
Hepatology at the London Medical School concluded - and
the balance of the evidence shows - from his
comprehensive recent review of the medical literature on
"Turmeric, an approved food additive, or its
component curcumin, has shown surprisingly beneficial
effects in experimental studies of acute and chronic
diseases characterized by an exaggerated inflammatory
reaction. There is ample evidence to support its
clinical use, both as a prevention and a treatment".
Note: Some curcumin supplements also contain piperine,
for the purpose of increasing the bioavailability of
curcumin, and piperine may also increase the
bioavailability and slow the elimination of a number of
drugs, (for example, phenytoin (Dilantin), propranolol
(Inderal) and theophylline).
with the "Dark Side" Considerations and Findings of
Somasundaram and López-Lázaro
In a study of
cultured breast cancer cells, curcumin inhibited
apoptosis induced by various chemotherapeutic agents
campothecin (CPT), mechlorethamine (Mustargen) and
doxorubicin (Adriamycin) at concentrations of 1-10
micromoles/liter, as found by Somasundaram and
at the Lineberger Comprehensive Cancer Center using an
in vivo model of human breast cancer.
findings are challenged by the more recent results of
Choudhuri et al.62
who observed that curcumin selectively increases p53
expression of carcinoma cells and releases cytochrome c
from mitochondria, an essential requirement for
apoptosis, leading the authors to conclude that curcumin
may have a possible therapeutic potential in breast
cancer patients, given the finding of the study that
curcumin induces apoptosis in cancer cells sparing
normal cells. It is therefore not impossible that
curcumin may as the Somasundaram findings suggest
inhibit the apoptosis activity of the studied
chemotherapy agents, but that either (1) it as Choudhuri
has shown provides it's own powerful pro-apoptotic
activity, or (2) the overall cytotoxicity and
anti-proliferative activity of the chemotherapeutic
agents may be unimpaired significantly, as apoptosis is
only one of many anti-tumor mechanisms that any
oncotherapeutic agent may leverage in its anti-cancer
Thus, we note that besides the pro-apoptotic activity
anti-cancer activity of curcumin, curcumin appears to
inhibit cancer cell proliferation by
microtubule-inhibition (not unlike the action of the
class of taxanes), perturbing microtubule assembly
and in addition curcumin also demonstrates powerful
In addition, subtoxic concentrations of curcumin
sensitize cancer cells to the tumor necrosis
factor-related apoptosis inducing ligand
(TRAIL)-mediated apoptosis; TRAIL, also known as Apo2L,
is a member of the Tumor Necrosis Family (TNF) family
and can induce apoptotic cell death in a variety of
cancer cell types, and the activity of curcumin in
enhancing TRAIL-mediated apoptosis appears to be an
outgrowth of its induction of reactive oxygen species
(ROS), generating reactive oxygen intermediates in
cancer cells with the associated oxidative stress
playing a role as a common mediator of apoptosis65.
In addition, re
the Somasundaram findings, these have been taken up and
extended by Miguel López-Lázaro and Estefanıa
Burgos-Morón and colleagues66
in Seville, Spain, who have coined the term the "dark
side" of curcumin for the set of adverse/negative
effects associated with curcumin, and echoed in the
reports from Marc Diederich and Marie-Hélène Teiten and
in Luxembourg, among others. It is claimed that by
these authors that curcumin blocked, in a dose- and
time-dependent fashion, the generation of ROS (reactive
oxygen species) which is otherwise induced by the
cyclophosphamide (CTX) and certain other
chemotherapeutic agents in MCF-7 (endocrine), MDA-MB-231
(triple negative), and BT-474 (HER2+) human breast
cancer cells, and consequentially that such
ROS-generation blockade (coupled with blockade of JNK
function) thereby prevented breast cancer cells from
critical appraisal suggests that there are several
fundamental issues raised by these claims that affect
Somasundaram findings, the application of curcumin
itself did not induce apoptosis, yet in such mammary
models curcumin-induced apoptosis is strongly
evidenced in the aggregated data to date; thus
leaving unclear why in this model, despite the claim
of curcumin-inhibited apoptosis of the intrinsic
apoptosis expected and systematically manifested in
active chemotherapy agent cyclophosphamide, there is
no observed pro-apoptotic activity as expected from
curcumin itself independent of cyclophosphamide,
suggesting a significant methodological problem with
and questionable status for this widely cited
study. Yet, data shows68
that curcumin inhibits the AP-1 transcription
factor known to be involved in apoptotic program and
regulation, also inhibiting the NF-kB
transcription factor involved in pro-survival and
apoptotic pathways, and recent data has found that
curcumin represses histone
acetyltransferase-dependent chromatin transcription
via inhibition of its p300/CREB-binding protein
which plays critical role apoptosis, cell cycle
control, differentiation, and other cellular
phenomena. See also below for other findings
on curcumin-induced apoptosis contrary to the
Hui Xaio and
in China investigated the antiproliferative effect
of curcumin combined with cyclophosphamide on the
growth of a human lymphoma cell line (HT/CTX) with
drug resistance, finding that that the combination
of curcumin + CTX had an additional synergistic
inhibitory effects on the proliferation and cell
cycle distribution of the lymphoma cells, and that
curcumin could enhance cyclophosphamide (CTX)
toxicity via inhibition of FA/BRCA (Fanconi
anemia/BRCA) DNA damage repair pathway, realized by
suppression of FANCD2 monoubiquitination, the
FA/BRCA pathway known to play a critical role in the
cellular response to replicative stress induced by
DNA alkylating agents like cyclophosphamide (CTX),
thus greatly influencing drug response in cancer
therapies. Curcumin + CTX increased the apoptosis
inducing effect on the HT/CTX lymphoma cells and in
addition effectively reversed multiple drug
resistance of HT/CTX cells, this in contrast to
either curcumin or CTX alone which was absent any
enhanced apoptosis and which moreover was not
inhibitory of the FA/BRCA pathway.
These findings speak directly to curcumin-induced
synergistic induction of apoptosis in concurrent
administration with cyclophosphamide, in
contradistinction to the claimed blockade of
cyclophosphamide-driven apoptosis in the dark side
findings cited (and it would therefore have to be
demonstrated why curcumin + cyclophosphamide would
block CTX-induced apoptosis in breast cancer cells
but synergistically enhance CTX-induced apoptosis in
lymphoma cells. Comparable claims are made by
Somasundaram and López-Lázaro / Burgos-Morón among
others of curcumin's interference with the
pro-apoptotic activities of other
chemotherapies such as paclitaxel (Taxol), although
we have divergent reports such as those of Srinivas
Ganta and colleagues70,71
at Northeastern University of curcumin-induced
enhancement of paclitaxel efficacy in resistant
ovarian cancer cells, enhancing the cytotoxicity in
wild-type and resistant cells by promoting the
/ Burgos-Morón suggest that the negative, “dark
side", effects of curcumin are mediated by several
mechanisms, including inactivation of the
tumor suppressor protein p53. But this is
equivocal: as noted in Beatrice Bachmeier's recent
curcumin can up-regulate the expression of p53 as
well as its acetylation, and more directly,
Tathagata Choudhuri and colleagues73
have in fact demonstrated curcumin-induced apoptosis
in the MCF-7 breast cancer cell line in which
expression of wild-type p53 can be induced, with the
induced apoptosis accompanied by an increase in p53
level as well as its DNA-binding activity followed
by Bax expression at the protein level, showing
therefore curcumin induced apoptosis in tumor cells
via a p53-dependent pathway in which Bax is the
downstream effector of p53, and confirming that p53
signaling acting via Bax activation is essential for
the apoptogenic effect of curcumin. But given
that the Somasundaram study tested MCF-7 breast
cancer cells, it would therefore be expected that
curcumin-induced apoptosis would be observed since
Choudhuri used this same cell line with observed
curcumin induced apoptosis via a p53-dependent
pathway, contrary to the Somasundaram findings and
to the claim made by López-Lázaro / Burgos-Morón of
curcumin-induced p53 inactivation.
concerns what is elided in the Somasundaram and
López-Lázaro / Burgos-Morón considerations, namely
the well-evidenced pleiotropic activity of curcumin,
which has been demonstrated to effect numerous
molecular pathways and targets inside the cell,
besides just apoptosis, and which we and innumerable
other researchers have documented extensively, and
which suggests that even if the argument for
curcumin inhibition of cyclophosphamide-induced
apoptosis were without methodological problems - and
our considerations here suggest the contrary - it
would nonetheless not follow that the net anticancer
effect of curcumin even in a concurrent CTX
environment would not be positive, given for example
curcumin's well-evidenced angiogenic activity, or
its subtle interference with the micro-RNA
system, its transcriptional inhibition of tumor
progression, its inhibition of MMP expression,
coupled with both anti-invasive and anti-metastatic
activities, interference with the inflammatory
mechanisms of tumor pathogenesis, potential reversal
of multi-drug resistance (MDR)among many others,
creating a complex web of processes
influencing multiple major moleclar pathways
converging on and promoting carcinogenesis and
tumorigenesis and malignant transformation.
still another issue at play here in the Somasundaram
and López-Lázaro / Burgos-Morón considerations and
findings: these, and many others, are based on the
assumption that apoptosis is characterized, and its
presence detectable, by (oligonucleosomal) DNA
degradation. But cell death can occur independently
of DNA degradation: curcumin can induce cell death
of Jurkat cells despite a simultaneous inhibitory
effect on DFF40/CAD endonuclease activity74,75,
suggesting that curcumin induces the apoptotic
pathway but, at the same time, protects cells
against (oligonucleosomal) DNA degradation
(apparently inhibiting DFF40/CAD endonuclease
activity of without blocking its DNA(17) binding)
and further demonstrating that the symptoms of cell
death - the apoptogenic signature, as it were -
induced by curcumin can be both divergent and also
dependent on the cell context, possibly accounting
for the apparent discrepancy of evidentiary data on
curcumin-based protection against cell death.
The dark side
considerations raised by Somasundaram and
López-Lázaro / Burgos-Morón are predicated on the
use of traditional curcumin extract, with no posited
standardization of the curcuminoid component,
and no bioavailability enhancement. Yet there
are widely used curcuminoid-standardized curcumin
formulations such as Sabinsa-certified formulations
with piperine (Bioperine) bioavailability
enhancement, and curcumin phospholipid complex (CPC)
formulations commercially as BCM-95-standardized
phospholipid-based curcuminoids, as well as
liposomal curcuminoid formulations (commercially,
Meriva), as well as several nanoparticle forms,
among many others, and these dramatically increased
curcuminoid availability. For example, a human
clinical pilot cross-over trial76
conducted by Benny Antony and colleagues in India,
of a commercial curcumin-phospholipid complex
formulation, BCM-95®CG (Biocurcumax™) which also
leverages the synergism between the sesquiterpenoids
in the form of turmeric essential oils and the
curcuminoids themselves, found that, compared to
standard (free) curcumin and to a
curcumin-lecithin-piperine formula (comparable to
Sabinsa-certified curcuminoids), the relative
bioavailability of curcumin-phospholipid complex was
6.93-fold compared to normal curcumin and about
6.3-fold compared to curcumin-lecithin-piperine
formula. Furthermore, even if we assume a
traditional curcumin extract, the fact as cited by
these authors that no curcumin nor curcumin
metabolites were detectable in blood or urine does
not foreclose potential antitumor activity; and in a
human volunteer trial77
at the Cytokine Research Laboratory (MD
Anderson), brain uptake of curcumin after 2 min was
increased by 48% due to coadministration of piperine
relative to that with out piperine). Thus the
Ricky Sharma at the University of Leicester and
of curcumin extract in refractory advanced
colorectal cancer patients, as well as the Phase II
trial from Navneet Dhillon at MD Anderson and
of curcumin extract in advanced pancreatic cancer,
found evidence of potential benefit.
This raises a
related point, put forth repeatedly by López-Lázaro
/ Burgos-Morón, that the concentrations of curcumin
and its metabolites achievable outside the
gastrointestinal tract by oral extract consumption
are simply insufficient to provide significant
antitumor activity, citing that "the
plasma concentrations of curcumin in people taking
relatively high oral doses of curcumin are very low,
typically in the nanomolar range. This means that
the oral administration of curcumin does not lead to
cytotoxic concentrations outside the
This is a familiar charge, made also in connection
with the curcumin dosing in pancreatic cancer study,
namely that the biological activities observed are
less likely to be due to curcumin, given that the
serum levels observed are only in low nanogram range
(in that study curcumin was coadministered with
gemcitabine (Gemzar)). But there is reason to
believe that serum levels of curcumin observable in
vivo in human patients cannot be directly compared
with those in vitro in the cell culture medium, in
part understandable when we appreciate that exposure
of cells to curcumin in cell culture
models/experiments is generally only short-term,
rarely above 24 -72 hours, as opposed to the
standard long-term exposure of even up to 6 months
in humans, and more critically, curcumin cell/tissue
levels rather than serum/cell culture levels are
more relevant. So in the above cited Sharma
colorectal cancer study, even though the
concentration of 3600 mg/d curcumin in normal
colorectal tissue was 12.7 +/- 5.7 and in malignant
colorectal tissue 7.7 +/- 1.8 nmol/g, these low
doses had pharmacological activity in colorectum as
measured by effects on levels of M(1)G and COX-2
Thus curcumin pharmacokinetics observed in tissues
after i.p. administration cannot be compared
directly with those observed after gavage or dietary
criticisms of the dark side perspective presented above
and our judgment for reasons specified that the
claims are, in the face of the aggregated cumulative
evidentiary base, unconvincing and the divers claims put
forth not sufficiently robustly demonstrated, exhibiting
as they do the serious methodological flaws we have
discussed here, nonetheless Somasundaram and
López-Lázaro / Burgos-Morón (and to a lesser
extend Diederich/Teiten via favorable citation) are to
be commended in raising awareness of the often
overlooked consideration that for any oncotherapeutic
agent whether traditional or CAM-based, the deployment
decision always involves a weighing of the benefit/harm
ratio and that clinicians should therefore obliged
themselves to master the relevant body of data on the
issue of the benefit/harm ratio to permit an
open-minded, candid, and informed discussion with the
patient in determining, in consultation, the best
choice relative of course to the context (where
patients in more advanced disease settings may accept a
higher degree of risk of potential harm or adverse
interaction than those in earlier stage disease). That
said, the overwhelming balance of the evidence to date
continues to support the safety and efficacy of various
curcuminoid preparations as adjunct oncotherapeutic
and the P450 Cytochrome System: What We Know
Curcumin is a
known powerful inhibitor of the carcinogen-activating
enzymes CYP1A1, CYP1A2, and CYP2B2, which like other
inhibitors of these isoenzymes, forms part of its basis
of favorable activity in the inactivation of carcinogens
(such as tobacco carcinogens82.
Curcumin is also one of several flavonoids, in addition
to quercetin, resveratrol and apigenin that were
investigated for their ability to induce CYP3A4 in human
hepatocytes, but it was determined that only quercetin
produced accumulation of CYP3A4 mRNA, as demonstrated by
Judy Raucy of the California Toxicology Research
Institute / CTRI83,
so curcumin appears to lack significant CYP3A4 activity.
Despite the lack
of CYP3A4 induction as demonstrated by the above-cited
findings of Judy Raucy at CTRI and others, some authors84,85
have continued to raise concern about curcumin's
theoretical potential for adverse hepatic-enzyme
mediated interactions. In this connection, it is
critical to differentiate between the
which are represented by
and other Curcumas except for
versus curcumin as the phenolic compound isolated from
the rhizomes of Curcumas, since Xiao-Long Hou and
at Osaka University demonstrated that curcumin as
opposed to Curcumas regulate the function of P-gp in
completely opposite ways; similarly, as to effects over
the cytochrome p450 cytochrome system, the same team
concluded that "both
Curcuma extracts and curcumin treatment had no influence
on CYP3A4 mRNA expression"
and that curcumin was not the major compound responsible
for putative enzyme inhibitory effects87.
Furthermore, Regina Appiah-Opong and colleagues88
at the Leiden/Amsterdam Center for Drug Research (LACDR)
evaluated the potential hepatic enzyme interactions of
curcumin decomposition products, concluding that
"In spite of
the significant inhibitory activities shown towards the
major CYPs in vitro, ... given the reported low systemic
exposure of the liver to curcumin . . . The
decomposition products of curcumin showed no significant
inhibitory activities towards the CYPs investigated, and
therefore, are not likely to cause drug–drug
interactions at the level of CYPs”. Therefore,
we conclude, in agreement with these and other findings,
that the weight of the evidence suggests that clinically
relevant DDIs involving curcumin, and in particular
curcuminoids (as opposed to raw Curcumas) are improbable
and that the evidence base is devoid of any clinical
data of significant DDI interactions exerted by curcumin
resveratrol, it selectively suppresses the
transcriptional activation of cytochrome CYP1A189,
also inhibiting COX-1 and COX-2 enzymatic activity, and
also suppressing the induction of the oncogenic NF-kB
transcription factor, with antiproliferative,
proapoptotic, and antiaromatase activity. Indeed, its
well-evidence antitumor activity is based in part on its
inhibition of both the constitutive and the induced
expression of CYP1A1 and CYP1B1, commonly overexpressed
in breast and many other cancers, in a dose-dependent
while its specifically anti-aromatase activity is due to
the enzyme-level inhibition of the CYP19 aromatase
enzyme and possibly also by decreasing mRNA CYP19
expression at the transcription level96-98.
-- Resveratrol, CYP19, Aromatase, and Estrogenicity
With respect to resveratrol, it should be noted that
Barry Gehm and colleagues99
at Northwestern first suggested that resveratrol
exhibits variable degrees of estrogen receptor agonism
in different test systems, and may have estrogenic
activity in vitro, but the later in vivo results
from Russell Turner's team at Mayo100
found, in contrast to prior in vitro studies,
that resveratrol has little or no estrogen agonism on
reproductive and nonreproductive estrogen target tissues
and may be an estrogen antagonist, and this lack of
estrogenic activity of resveratrol has been
cross-confirmed by Martina Böttner at the University of
Lübeck and colleagues101,
and by Krishna Bhat and colleagues102
at the University of Illinois who found in vivo evidence
of resveratrol acting as a chemopreventive SERM.
Furthermore, Yu Wang and colleagues103
at The Chinese University of Hong Kong established that
resveratrol inhibited the enzyme activities and reduced
the mRNA abundance of CYP19, thus functioning as a
bilevel inhibitor of aromatase, reducing localized
estrogen production in breast cancer cells. And most
recently, Alois Jungbauer's team104
in Austria found that only 2% of the estrogenic activity
of red wines was due to trans-resveratrol, thus
suggesting that the estrogenicity of red wines is not
due to resveratrol, but rather to the wine flavonoid
-- Caution - Resveratrol and Paclitaxel
preclinical study of resveratrol from Masuyuki Fukui and
at the University of Kansas found that that resveratrol
strongly diminished the susceptibility of certain breast
cancer cells, including triple negative (MDA-MB-231
cells)" to paclitaxel-induced cell death in culture, and
also in vivo in mice (not observed in non-TNBC MCF-7
cells), and although this has not been demonstrated in
the human clinical setting, it suggests caution in
co-administration of resveratrol and paclitaxel (Taxol)
(and possibly by extrapolation with other taxanes,
although these were not studied).
boswellic acids, derived from the Boswellia
(frankincense) species do not appear to exhibit any
significant CYP-mediated dependencies106.
However (see more
below), phenytoin (Dilantin), mifepristone (Mifeprex),
omeprazole (Prilosec), clotrimazole (Lotrimin),
lovastatin (Mevacor), atorvastatin (Lipitor) and
mevastatin (Compactin) were all capable of enhancing the
expression of hepatocyte CYP3A4 mRNA.
EGCG and Green
Tea Extracts and Components
Safety and Interaction
Sherry Crow and colleagues107
at the Arizona Cancer Center observed that preclinical
studies suggested that green tea or green tea catechins
can modulate the activities of drug-metabolizing
enzymes, and they conducted a clinical study to
determine the effect of repeated green tea catechin
administration on human cytochrome P450 (CYP) enzyme
activities, finding that repeated green tea catechin
administration (at a dose that contains 800 mg
epigallocatechin gallate (EGCG) daily) is not likely to
result in clinically significant interference with the
disposition of drugs metabolized by CYP enzymes (CYP1A2,
CYP2D6, CYP2C9, and CYP3A4).
with Chemotherapy and Reversal of Drug Resistance
Yuying Mei et al.108
explored the reversal effects on multidrug resistance
(MDR) via the antioxidant capacities of tea polyphenols,
and EGCG in particular, based on the observation that
drug resistance cells undergo oxidative stress,
confirmed in doxorubicin (Adriamycin)-induced
intracellular concentration of ROS (reactive oxygen
species), and this MDR was reversed by tea polyphenols
and EGCG. This was confirmed in the study by Feng Qian
at the East China University of Science and Technology
who investigated the molecular mechanism of EGCG and its
activity in the reversal of P-glycoprotein (P-gp)
mediated MDR (multidrug resistance), finding that in
vitro EGCG potentiated the cytotoxicity of doxorubicin
to drug-resistant KB-A1 cells, and that in a KB-A1 cell
xenograft model, EGCG addition enhanced the efficacy of
doxorubicin, increasing the concentration of doxorubicin
in resistant tumors, suggesting that EGCG modulates the
function of P-gp and reverses P-gp mediated multidrug
resistance in human cancer cells. And these findings
themselves further confirm the earlier in vivo results
of Qiang Zhang and colleagues110
who found that EGCG increased by 51% the concentration
of doxorubicin in resistant tumors and also increased
doxorubicin-induced apoptosis in those tumors, with the
doxorubicin/EGCG combination being well-tolerated, and
concluded therefore that EGCG chemosensitizes resistant
tumor cells to doxorubicin.
Similar results were established in animal studies of
leukemia, with doxorubicin-resistant leukemia cells
(P388) by Yasuyuki Sadzuki and colleagues111
at the University of Shizuoka Japan, who found that
green tea components (including caffeine, theanine, and
EGCG) increased the doxorubicin-induced efficacy against
these cells via an increase in the doxorubicin
concentrations in the tumors and hence increasing the
doxorubicin-induced antitumor activity. These results
were confirmed and extended in the research of the Mayo
Clinic team of Yean Lee and colleagues112
who observed that it has been previously established
that CLL (chronic lymphocytic leukemia) cells synthesize
and release VEGF (vascular endothelial growth factor)
under normoxic and hypoxic conditions, and that CLL B
cells also express VEGF membrane receptors (VEGF-R1 and
VEGF-R2) which are spontaneously phosphorylated on these
cells, suggesting that these cells are using VEGF as a
survival factor, given that VEGF significantly increases
the apoptotic resistance of CLL B cells. They therefore
evaluated the impact of EGCG
(epigallocatechin-3-gallate), a known receptor tyrosine
kinase (RTK) inhibitor, on the VEGF receptor status and
viability of CLL B cells, finding that EGCG
significantly increased apoptosis/cell death in 8 of 10
CLL cell samples and suppressed both the Bcl-2 (B-cell
leukemia/lymphoma-2), XIAP (X-linked inhibitor of
apoptosis protein), and Mcl-1 (myeloid cell leukemia-1)
proteins in the CLL cells, as well as VEGF-R1 and
VEGF-R2 phosphorylation (incomplete suppression); they
concluded from these findings that VEGF signaling
regulates CLL cell survival signals and that
interruption by EGCG of this autocrine pathway results
in caspase activation and subsequent leukemic cell.
And more recently TD Shanafelt and colleagues113
at the Mayo Clinic (Rochester, MN) confirmed the ability
of EGCG to induce apoptotic cell death in the leukemic
B-cells in patients with CLL (chronic lymphocytic
leukemia (CLL)). Indeed, the researchers document
several patients with low grade B-cell malignancies seen
in clinical practice at the clinic with steady clinical,
laboratory, and/or radiographic evidence of progression
who on their own initiative, began EGCG consumption and
subsequently developed objective clinical response.
Moreover, Tae Heung Kang and Chinese and Korean
and researchers at Johns Hopkins found that a
multimodality treatment regimen using DNA vaccination in
combination with EGCG was effective in inhibiting large
tumor growth, inducing tumor cellular apoptosis in a
dose-dependent manner and enhanced tumor-specific T-cell
immune response and enhanced antitumor effects,
resulting in a higher cure rate than either
immunotherapy or EGCG alone, as well as providing
long-term antitumor protection in cured mice.
Atorvastatin (Lipitor) is another drug
metabolized over the p450 cytochrome pathway and used by
many breast cancer patients, and is known to be a potent
CYP3A4-inhibitor, entailing significant potential for
adverse interaction with other agents dependent on
CYP3A4-mediated metabolism. One such, as we discussed
above, is the aromatase inhibitor (AI) exemestane
(Aromasin), but there are many others: restricting my
attention to those with known clinically relevant
interactions, these are:
Benzodiazepines (anti-anxiety agents),
Chlorpheniramine (Chlortrimeton, an antihistamine),
Calcium channel blockers (for cardiovascular disorders),
Tamoxifen (tamoxifen has extremely subtle and complex
pharmacokinetics and pharmacodynamics) and
Vincristine (Oncovin], and
Grapefruit juice, which is one of the most powerful
CYP3A4-inhibitors ever discovered (with even many
recorded fatal interactions).
One workaround is
to explore switching to simvastatin (Zocor) or
pravastatin (Pravachol), two statins without significant
p450-mediated metabolism. Another option is
rosuvastatin (Crestor), the newest and most potent of
the FDA approved statins; it has been established that
rosuvastatin is not extensively metabolized by
cytochrome P450 isoenzymes, and so and inhibitors of
these isoenzymes do not affect it in clinically
significant ways, and although it is minimally - and
clinically insignificantly - metabolized in the CYP2C9
isoenzyme pathway and to lesser extent in the CYP2C19
isoenzyme pathway, It is not metabolized by means of
cytochrome P450 (CYP) 3A4, and furthermore rosuvastatin
does not have any inhibitory or inducing effects on the
cytochrome P450 hepatic enzyme system.
It should be noted that several studies have raised some
safety issues concerning statins including rosuvastatin,
most notably the postmarketing analysis of Alawi
Alsheikh-Ali and collegaues116,117
at Tufts which reviewed statin-associated events
reported to the FDA during rosuvastatin’s first year on
the market. The adverse event reports for
rhabdomyolysis, proteinuria, nephropathy, or renal
failure were higher for rosuvastatin than for
atorvastatin (Lipitor), simvastatin (Zocor), or
pravastatin (Pravachol). In answer to a petition filed
with the FDA by Health Research Group of Public Citizen,
the FDA acknowledged that postmarketing rosuvastatin
kinetics studies found that Asian Americans experience
blood levels of the drug twice as high as non-Asians,
potentially predisposing to severe myopathy, and for
that reason, the FDA advises that rosuvastatin be used
only in low doses in Asian Americans, although Scott
with the Center for Human Nutrition, and others119,120
in the same vane, provides some prudent perspective on
these safety issues. See also the recent cautious and
provocative assessment by Mark Golstein of statins and
cancer risk, and the sobering conclusion that "there
is ample evidence that statins may promote cancer in
certain segments of the population. Currently, the
indications for statin therapy are based on lipoprotein
levels, prevalent cardiovascular disease, other vascular
risk factors, and family history. Maybe it is time for a
new paradigm that also includes age extremes, prevalent
cancer, a past history of cancer, and overall
Antisecretory (PPI and H2RA)
PPIs (proton pump
inhibitors) including omeprazole (Prilosec),
lansoprazole (Prevacid), pantoprazole (Protonix), and
esomeprazole (Nexium), and most H2RAs (histamine-2
receptor antagonists) including cimetidine (Tagamet),
famotidine (Pepcid), and nizatidine (Axid) have
CYP2C19-mediated hepatic metabolism and so represent
potential adverse interaction with letrozole (Femara)
which is also CYP2C19-dependent in part for its
activity. The PPI rabeprazole (Aciphex) is mainly
metabolized via a non-enzymatic pathway to
thioether-rabeprazole, with relatively small CYP2C19
involvement; however even with rabeprazole (Aciphex)
there is some theoretical potential for CYP2C19-mediated
interaction, although this appears much less so than
with any of the other PPIs. Of the H2RAs,
ranitidine (Zantac) is considered a weak CYP2C19
inhibitor and so may be safer than others in
coadministration with letrozole (Femara), but Slobodan
notes that "Although the results obtained with
ranitidine showed a low inhibitory potential, drug-drug
interactions were reported in some cases", and the
same review suggests that famotidine (Pepcid) and
nizatidine (Axid) also possess
"a weak cytochrome P450 inhibitory potential and a low
drug-drug interaction potential",
while cimetidine (Tagamet)
"is a strong
inhibitor of the CYP2D6 and 2C19 enzymes in vivo".
Thus with respect to the H2RAs, the best we can conclude
on the evidence is that cimetidine (Tagamet) appears to
exhibit the greatest potential for adverse drug
interactions across especially the CYP2D6 and CYP2C19
enzymes, while ranitidine (Zantac) appears to be a weak
CYP2C19-inhibitor,as do famotidine (Pepcid) and
nizatidine (Axid) although there is nonetheless some
residual small possibility for adverse drug interactions
with all agents, especially cimetidine (Tagamet)122-129.
Metaxalone (Skelaxin) - like most muscle relaxants
(carisoprodol (Soma, Rela), cyclobenzaprine (Flexeril),
orphenadrine (Norflex, Norgesic), and chlorzoxazone
(Parafon) - has CYP3A4-dependent metabolism, although
two - tizanidine (Zanaflex) and methocarbamol (Robaxin)
- are exceptions and could be used as safe alternatives;
however, tizanidine (Zanaflex) is mainly
while methocarbamol is metabolized via dealkylation and
Package Insert - Pharmacokinetics].
Phenyltoloxamine (Novagesic, Dologesic, Flextra,
Phenylgesic) when combined as it typically is with
acetaminophen (Tylenol) however is a weak CYP3A4
inhibitor, although a moderate CYP2D6 inhibitor,
although the contribution of moderate CYP2D6 inhibitor
and weak CYP3A4 inhibitor activity appears to be
essentially from the acetaminophen131,132.
As to sedative / hypnotics in the class of
benzodiazepines - such as alprazolam (Xanax),
chlordiazepoxide (Librium), clonazepam (Klonopin),
clorazepate (Tranxene), diazepam (Valium), lorazepam
(Ativan), midazolam (Versed), oxazepam (Serax),
temezepam (Restoril), and triazolam (Halcion) - the
safest from this drug interaction standpoint are
temezepam (Restoril) and lorazepam (Ativan), as these
are not significantly metabolized at all by the P450
cytochrome system of hepatic enzymes (both temezepam and
lorazepam directly undergo glucuronide conjugation), and
so can typically be used concurrently with other agents,
including oncotherapeutic ones, without interaction
and oxazepam (Serax) may also be relatively free of
hepatic enzymes interactions, as it - like lorazepam
(Ativan) - is not oxidatively metabolized by cytochrome
P450 but rather glucuronidated by glucuronyl
Note also that in addition to being a CYP3A4 substrate
as are most benzodiazepines, diazepam (Valium) has
additional dependencies over CYP1A2, CYP2C8/9, and
What of non-benzodiazepines such as zolpidem (Ambien),
Zopiclone (Lunesta), Zalephon (Sonata) and ramelteon
(Rozerem)? In contrast to most (but not all - see above)
benzodiazepines, these newer hypnosedatives are
biotransformed by multiple CYP isozymes in addition to
CYP3A4, so that CYP3A4 inhibitors and inducers would
tend to have a lesser effect in the aggregate on their
And Zolpidem (Ambien) even at extremely high dosing
levels of approximately 200 times maximum therapeutic
concentrations produced negligible or weak inhibition of
CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A, and is highly
unlikely to induce clinical drug interactions across
hepatic CYP enzymes P-gp mediated transport137,138.
As to ramelteon (Rozerem), a melatonergic (melatonin
receptor) agonist, the major isozyme involved in its
metabolism is CYP1A2, with the CYP2C subfamily and
CYP3A4 isozymes also involved to a minor degree139,140.
One caution however is coadministration of rameleon
(Rozerem) with a strong CYP3A4 inhibitor (such as
erythromycin, clarithromycin, ketoconazole,
itraconazole, telithromycin, atazanavir, indinavir,
nefazodone, nelfinavir, ritonavir, saquinavir,
voriconazole, and grapefruit juice) requires caution141.
Non-Narcotic Pain Relievers
-- Acetaminophen (Tylenol)
As noted above,
is a weak CYP3A4 inhibitor and a moderate CYP2D6
inhibitor. But a finer appreciation of acetaminophen's
pharmacokinetics strongly establishes that these
cytochrome P4540 hepatic enzymes pathways are of no
clinical significance: acetaminophen is metabolized in
the liver by two distinct pathways, 85% to 90% of a dose
being conjugation with activated sulfate and glucuronic
acid via a phase II reaction, with a small proportion of
metabolized by a phase I cytochrome P450 (CYP) reaction
to a reactive, electrophilic intermediate,
N-acetyl-p-benzoquinoneimine (NAPQI). And most
critically, recent human clinical data have clarified
that only the CYP2E1 isoenzyme plays any significant
role in acetaminophen's cytochrome P450 metabolic
pathway, via the reactive intermediary metabolite NAPQI,
and that the contributions of other cytochrome p450
isozymes of cytochrome P450 appear to be negligible142,
and hence the interaction of acetaminophen with other
agents over non-CYP2E1 hepatic enzyme pathways is likely
to be clinically insignificant143,
and we observe further that the contribution of the
CYP3A4 pathway to total NAPQI formation varies from 1%
to at most 20%144,145,146.
Note further that only a small percentage of
acetaminophen is converted to the NAPQI metabolite,
normally detoxified by hepatic glutathione (GSH), which
accounts in part for acetaminophen-induced hepatic
injury under certain circumstances, such damage not
being secondary to the drug (acetaminophen) itself but
rather to the NAPQI metabolite147,148,149.
-- Celecoxib (Celebrex)
Although no published studies have yet evaluated the
on CYP-metabolized drugs, it did not effect
CYP2C9-metabolized drugs (such as warfarin, a substrate)
in vivo. However celecoxib (Celebrex) inhibits
CYP2D6 and so may increase serum concentrations of
CYP2D6 substrates, including many SSRI and tricyclic
antidepressants, antifungals, antipsychotics, narcotic
analgesics such as codeine, and ß-blockers150.
But in balance, we note that there is some reassurance
from the fact that no safety signals concerning adverse
interaction with AI therapy have been to date raised to
date from the CAAN Trial, the NCI-based
letrozole-Celecoxib Trial, and the UK-based NEO-EXCEL
Trial, all combining aromatase inhibitors with
concurrent celecoxib (Celebrex).
-- Other Analgesics
is predominantly metabolized by CYP2C9151,
by CYP2C9 and CYP1A2152,
CYP2D6 is primarily responsible for M1
(O-desmethyl-tramadol) formation, with M2
(N-desmethyl-tramadol) formation catalyzed by CYP2B6 and
CYP3A4, these being the two primary tramadol metabolites153.
Diphenhydramine is a CYP2D6 and CYP3A4 inhibitor , it is
for that reason problematic with letrozole (Femara) -
which is also partially metabolized by the hepatic
CYP2D6 and CYP3A4 enzymes - as to potential adverse
interaction and may interfere with letrozole activity
(and note that the official product labeling of
letrozole (Femara) carries a warning about this
potential adverse interaction from coadministration with
The leukotriene receptor antagonist montelukast
(Singulair) exhibits weak but noninhibitory activity on
CYP1A2, CYP2A6, CYP2C19, CYP2D6, and CYP3A4-catalyzed
with some comparatively weak induction of significant
CYP2C9 inhibition in vitro, although it does not affect
the pharmacokinetics of the CYP2C9 S-warfarin substrate,
and does not in addition inhibit CYP2C8-mediated
metabolism and so behaves as a selective CYP2C8
inhibitor, and therefore in the aggregate is
considered a safe agent without significant drug-drug
Budesonide is a corticosteroid, found in micronized
form, along the selective beta2 agonist, formoterol
fumarate dihydrate, in Symbicort, and also in other
inhaler form allergy / asthma medications such as
Rhinocort and Pulmicort,and also for treatment of
Crohn's Disease under the Entocort label. It is
predominantly metabolized by the CYP3A4 isoenzyme158-161.
The antihistamine cetirizine (Zyrtec) appears to not
exhibit adverse hepatic cytochrome p450 mediated
agents such as - aspirin, clopidogrel (Plavix),
dipyridamole (Persantine), and ticlopidine (Ticlid) -
exhibit some significant cytochrome P450 hepatic enzyme
dependencies, typically CYP2C19- and CYP3A4-mediated.
Clopidogrel (Plavix) appears to be mainly
as is low-dose aspirin165,
both of which also appear to have some CYP3A4
And both clopidogrel (Plavix) and ticlopidine (Ticlid)
are also CYP2B6 inhibitors168,
while clopidogrel (Plavix) is also a CYP2C9 inhibitor169,170.
With respect to clopidogrel (Plavix) it should also be
noted that the OCLA (Omeprazole CLopidogrel Aspirin)
Study that omeprazole (Prilosec) significantly decreased
certain clopidogrel platelet inhibitory effect171,172,
although the precise clinical significance of this has
not been as yet fully clarified. Finally, ticlopidine
(Ticlid) is selective for CYP2C19173,
levothyroxine (Synthroid) does not appear to be a
substrate for any major drug metabolizing CYP-enzyme175.
(Vitamin D3) itself does not appear to have any
significant biological activity, but rather the
principal circulating form of vitamin D3 is
25-hydroxyvitamin D (also referenced as
25-hydroxycholecalciferol), or 25(OH)D for short,
another reference for calcidiol, which is activated by
renal 1 α-hydroxylase (also know as the enzyme vitamin
D-25-hydroxylase) to form the metabolically active form
of vitamin D3, 1,25-dihydroxvitamin D (1,25(OH)2D), aka
calcitriol. Thus there is a two-phase hydroxylation of
cholecalciferol: (1) in the liver to
25-hydroxycholecalciferol [25(OH)D3] and then (2) in the
kidney to 1,25-dihydroxycholecalciferol (1,25(OH)2D) –
calcitriol, and this (calcitriol) being the active form
of vitamin D3 which exerts its effects by directly
binding to the vitamin D receptor (VDR)176,177,178.
It is the mitochondrial enzyme
that catalyzes 1-hydroxylation in the kidney, and in
appears to be the biologically relevant vitamin D
with another hepatic enzyme
(known as 25-hydroxyvitamin D-24-hydroxylase) regulating
the concentrations of both the precursor 25(OH)D and the
hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, and hence
playing an important role is vitamin D homeostasis180,181.
NCI Cancer Therapy
Evaluation Program (CTEP)
- uniquely, against all other authoritative
sources - lists
inhibitor in their “Cytochrome P450 Drug Interaction:
Tables List of drugs that may have potential CYP2C19
interactions (Appendix C; Word .doc file)”182.
This is in error and devoid of methodologically robust
evidentiary support, and indeed appears medically
misreasoned since, as noted above, cholecalciferol is a
precursor and itself has no significant biological
activity, and so the important pharmacokinetics are
those of 25(OH)D (25-hydroxyvitamin D /
25-hydroxycholecalciferol), aka calcidiol, and the
metabolically active form of vitamin D3, 1,25(OH)2D
(technically, 1,25-dihydroxvitamin D, aka calcitriol,
and it is established that these are mediated by
CYP27B1, CYP24A1, and CYP2R1, and so any hepatic enzyme
dependency of the precursor agent cholecalciferol
(Vitamin D3) itself is clinically of no significant
consequence or relevance.
Our review of this issue suggests that the authority of
the NCI CTEP inclusion appears to be a single early
the clinical relevance of this isolated, and never to
date cross-confirmed or validated, study investigating
the effects of a number of agents including
cholecalciferol on xenobiotic oxidations catalyzed by 12
recombinant human cytochrome P450 enzymes and by human
liver microsomes is unclear and has not been to date
established, and cannot stand against the weight of the
evidence base. And indeed our own review has
revealed that this aberrant finding is directly refuted
by an independent team under Shin-ichi Kamachi184
with BCG-Japan: fourteen P450 isoenzymes (CYP1A1, 1A2,
1B1, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Val,
2D6-Met, 2E1, 3A4, 4A11) were tested for their
25-hydroxylation activity of 1-OH-D3, and it was
concluded that (1) none catalyzed the 25-hydroxylation
reaction, and that (2) the 25-hydroxylation activity of
1-OH-D3 localized in the microsomal fraction appears to
be attributable to a cytochrome P450 other than those
tested in this study. Of course, unknown to the
investigators at that time (2001) later research which
we reviewed and cited above has established the critical
dependencies to be those of the
CYP27B1, CYP24A1, and
on CYP2C19, CYP2D6 or CYP3A4 among others.
Of the several beta-adrenergic blocking agents -
is the classic CYP2D6 substrate, almost universally used
as the model substrate for this hepatic enzyme although
all these beta blockers are CYP2D6 substrates to
different degrees. Among the β-blockers, metoprolol is
most highly CYP2D6-dependent (70 - 80% metabolized over
It is now recognized that there are many potentially
clinically significant food-drug interactions188,
since drug-food, drug-herb or drug-drug interactions can
occur when any orally administered CYP3A substrate is
given concomitantly with an inhibitor or inducer of
intestinal CYP activity189,
and potentially adverse interactions have been raised in
hundreds of studies. To take one of dozens of
examples, several studies have shown that broccoli
increases CYP3A activity190-193,
and hence can adversely interact with a broad range of
CYP3A4-mediated oncotherapies, including as documented
above, taxanes (docetaxel (Taxotere), paclitaxel
(Taxol)), vinca alkaloids (vinorelbine (Navelbine),
vinblastine (Velban), vincristine (Oncovin)), and
aromatase inhibitors, all CYP3A4-mediated, as well as
tamoxifen which although mainly CYP2D6-mediated,
exhibits potential CYP3A-mediation in addition. So, for
example, the aromatase inhibitor exemestane (Aromasin)
which is extensively metabolized by CYP3A4, carries an
FDA label warning that
that induce CYP3A4 may significantly decrease exposure
similarly for vinorelbine (Navelbine) which carries the
FDA label warning that
be exercised in patients concurrently taking drugs known
to inhibit drug metabolism by hepatic cytochrome P450
isoenzymes in the CYP3A subfamily",
with comparable warnings for docetaxel
of docetaxel may be modified by the concomitant
administration of compounds that induce, inhibit, or are
metabolized by cytochrome P450 3A4",
and the other hormonal and chemotherapeutic agents we
identified above as CYP3A4-mediated in their metabolism194.
In addition to increasing CYP3A(4) activity as
documented immediately above, broccoli - like all
brassica vegetables - also increases CYP1A2 activity in
an adverse interaction since increased CYP1A2 function
is associated with increased risk for breast cancer196,
confirmed independently by the demonstration that CYP1A2
activity in postmenopausal women was positively
associated with mammographic density197.
Thus, food components like those of brassica /
cruciferous vegetables may exhibit potentially adverse
activities along multiple CYP pathways: both over the
p450 cytochrome hepatic enzyme system via CYP-mediated
interactions with concurrent oncotherapies, as well as
independently of any coadministration with oncotherapy,
via adverse increase of (among others) CYP1A2 activity
which is established as directly elevating breast cancer
risk. In both cases the adverse impact is mediate by
p450 CYP enzymes, but only the first is
interactive with concurrent oncotherapy, the second mode
capable of exerting adverse impact even in the absence
of any active therapy.
This same dual mode can be seen with other agents:
grapefruit juice (GFJ) exhibits strong - and strongly
adverse - impact via its antioxidant furanocoumarins
components bergamottin, naringin, and
dihydroxybergamottin. Given this, it would be prudent to
avoid all coadministration with, for example, exemestane
(Aromasin), and of course with the other chemotherapies
noted above as well as the vast number of other
CYP3A4-mediated drugs exhibiting adverse interactive
activity, as witness the well-known, extensively
documented, fatality of a 29-year healthy man and
allergy sufferer who consumed just two glasses of
grapefruit juice while taking terfenadine (Seldane)
antihistamine medication, which induced fatal cardiac
arrhythmias via prolongation in the QT interval, by
virtue of CYP3A4-mediated highly toxic elevated levels
And the window of potential exposure is wide: at least
24 hours, since 24 hours after ingestion of a glass of
grapefruit juice, 30% of its effect is still present and
and under some circumstances some small but
appreciable activity may still be present at 72 hours
But in a different mode of action, grapefruit (whole
fruit) consumption itself has been recently associated
with elevated risk of breast cancer in a large
prospective cohort study of over 50,000 postmenopausal
women from five racial/ethnic groups conducted by
at the USC Norris Comprehensive Cancer Center, which
found that grapefruit intake was significantly
associated with an increased risk of breast cancer for
subjects in the highest category of intake, which was
just one-quarter of one grapefruit or more per day, with
the minimal consumption of one quarter of a grapefruit
daily increasing the breast cancer risk by a distressing
30 percent, via clinically significant increases in
plasma estrogen concentration, at alarmingly higher
circulating estrogens levels. And although this single
study requires further confirmation in other trials to
be absolutely dispositive, given broad supportive
preclinical and pharmacokinetic data and compelling
molecular motivation, it would be prudent for women both
cancer-naive and especially those with breast cancer to
exercise extreme caution in any significant consumption
of dietary grapefruit203.
Given that dietary factors are estimated to account for
30% to 35% of cancer incidence, as found in the seminal
studies of Sir Richard Peto, UK's leading epidemiologist
and his colleague, the late Sir Richard Doll203,
these findings on the potentially adverse interaction of
dietary factors with various oncotherapeutics, and well
as the direct adverse potential of dietary components on
various human cancers, independently of any active
therapy or relevant interactions, are of especial weight
and pertinence in avoidance of associated disease and
f note, garlic (and other members of the Allium genus)
showed dose-dependent dual activity, elevating CYP3A4
mRNA at a lower dose of 0.1 µg/ml, whereas at higher
doses garlic produced a decline, and garlic has been
independently found to adversely increase the metabolic
elimination of the HIV protease inhibitor, saquinavir
(Invirase), a CYP3A4 substrate, in patients consuming
both the anti-retroviral and garlic concurrently205,
this study being the first (but not the last) to
demonstrate that garlic supplements, which are widely
used, might have a detrimental effect on concomitant
medications, expanding on the earlier findings of Brian
Foster and colleagues206
at Health Canada besides supplements, fresh and aged
garlic exhibited similar detrimental effect.
Foster study has further helped to clarify this issue:
the study tested 6 different garlic supplements (ranging
in dose from 10mg to 20mg, equivalent to 1000mg to
2000mg fresh garlic content) inhibited the cytochrome
p450 CYP2C19 enzyme by 21% to 53%, and concludes that "constituents
of garlic may not need to be present in high levels to
elicit a pharmacological effect in order to produce a
systemic or pre-systemic effect on drug disposition. The
potential for the garlic products examined in this study
to affect drug disposition may increase if used in
combination with one or more conventional therapeutic
products" and more importantly, that "that the
disposition of drugs . . . could be inhibited after the
co-administration with garlic or garlic products".
Note that the metabolism of the widely deployed
endocrine agent / aromatase inhibitor letrozole (Femara)
is in part CYP2C19-mediated, and so potentially
adversely affected by garlic coadministration.
In contrast with
these in vitro findings, David Greenblatt and his
at Tufts evaluated 8 water-soluble components of aged
garlic extract in order to asses potential to inhibit
cytochrome-P450 (CYP) enzyme activity, for the CYP1A2,
CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, observing
that none of the 8 garlic components produced >50%
inhibition even at high concentrations, except for
S-methyl-L-cysteine and S-allyl-L-cysteine, which
produced 20–40% inhibition of CYP3A compared to control.
They conclude from this that drug interactions involving
inhibition of CYP3A enzymes by aged garlic extract are
However, we note
(1) That although
their observation there is no available clinical
evidence for CYP3A inhibition in vivo by garlic or
garlic components is accurate, it should be remember
that there is no such in vivo data because no in vivo
trial has been conducted to settle the matter one way or
the other, so the absence of data for an in vivo
inhibitory effect is not to be construed as the presence
of positive data that shows no such effect occurs in
(2) That they consider the two exceptions (the
S-methyl-L-cysteine and S-allyl-L-cysteine garlic
components) of significant 20–40% inhibition of CYP3A as
"modest", but a reduction this large, were it to be
evidenced in vivo with oncotherapy, would be considered
quite dramatic and of grave concern given the narrow
therapeutic index of oncotherapeutic agents, and this
suggests at least a potential for adverse interaction
with such endocrine agents as anastrozole (Arimidex)
whose metabolism is CYP3A-mediated, exemestane
(Aromasin) which is CYP3A4-mediated, and the
CYP3A4-mediated chemotherapy agents the taxanes
docetaxel (Taxotere), paclitaxel (Taxol), nab-paclitaxel
(Abraxane), or any of the Vinca alkaloids vinorelbine
(Navelbine), vinblastine (Velban), and vincristine
(Oncovin), and the platinum agent carboplatin. Without
in vivo data to demonstrate no clinically significant
impact of this CYP3A/3A4-inhibitory activity, the
potential for adverse interaction remains (not that
although on at least one of these agents, docetaxel
(Taxotere) Michael Cox and coresearchers208
found that garlic did not significantly affect the
disposition of docetaxel, nonetheless as the authors
admit, it cannot be excluded that Allium vegetables like
garlic decreases the clearance of docetaxel in patients
carrying a CYP3A5*1A allele, and hence coadministration
is still problematic, as can not typically pre-identify
(3) The Greenblatt findings, with respect to CYP2C19
appear to be in direct contradiction to the Foster
findings cited above, although Breast Cancer Prevention
Watch notes this may be an artifact of the overly
permissive and broad definition of significant
interaction in the Greenblatt study, which is > 50%
inhibition. In contrast the Foster study found that the
6 garlic supplements (ranging in dose from 10mg to 20mg,
equivalent to 1000mg to 2000mg fresh garlic content)
inhibited the cytochrome p450 CYP2C19 enzyme by 21% to
53%, amounts they observe correctly could "elicit a
pharmacological effect in order to produce a systemic or
pre-systemic effect on drug disposition".
We see here a
classical difference of disposition: for Greenblatt,
potential interaction appear to have to exert very large
effects (> 50%) before perceived as clinically
significant, while for Foster a potential 20% or higher
reduction in the activity of a drug (and possibly lower)
is taken as significant in reductive capability; more in
contrast. Greenblatt takes an optimistic approach to the
issue of potential adverse interaction (based on in
vitro findings), not observing a notable hazard unless
there are explicit data that show an in vivo adverse
interaction, while Foster takes a cautionary perspective
until in vivo data were to show that the potentially
adverse interaction in vitro is not also found in vivo,
and absent such evidence, as here, views
coadministration as problematic.
Given the narrow
therapeutic index of oncotherapy agents, and their
potential impact on mortality, Breast Cancer Prevention
Watch would suggest erring on the side of caution: after
all, for years we have known about a well-documented
potentially adverse compromise of tamoxifen efficacy
when coadministered with SSRI antidepressants, but many
oncologists (but not David Flockhart, a principal in
these findings) argued that proactive data of a
clinically adverse interaction, coadministration should
continue without change (while as many said "the jury is
Others, including ourselves have reasoned otherwise,
noting that the absence of demonstration of harm is not
equivalent to the demonstration of no harm, and that
given the vital operation of tamoxifen, typically
administered over years, it would be imprudent to chance
coadministration with an SSRI only to learn that indeed
the interaction is significant, and adverse, at the
clinical level, as this may entail tamoxifen failure,
and even consequent patient mortality or disease
recurrence due to deployment of an efficacy-compromised
endocrine agent like tamoxifen.
On the basis
therefore of the above considerations, we agree with the
deductions of Sonnichsen and colleagues209
who conclude that
foodstuffs or food constituents, such as, for example,
grapefruit, Seville orange juice, red wine, alcoholic
drinks in general, or large quantities of caffeine and
garlic should be avoided during drug treatment",
in keeping also with the results of Alex Sparreboom's
at the NCI in their review, finding that garlic was one
of the natural agents with the "potential to
significantly modulate the activity of drug-metabolizing
enzymes (notably cytochrome P450 isozymes) and/or the
drug transporter P-glycoprotein" and which
"participate[s] in potential pharmacokinetic
interactions with anticancer drugs" and also with the
results of Zhou and who found potentially adverse
interaction of the dially sulfone component of garlic as
a CYP3A4 inhibitor, although an earlier study by
Markowitz and colleagues212
found in contradiction that garlic extracts were
unlikely to alter the disposition of coadministered
medications primarily dependent on the CYP2D6 or CYP3A4
pathway of metabolism. Such not wholly convergent
findings suggest the need for caution concerning
coadministration until in vivo / clinical data are
available to settle the issue.
As can be seen
from the above, although we have to date no decisive in
vivo / clinical data to either definitely show harm, or
the opposite, to definitively show
harm, there remains the potential for adverse
interaction between Allium vegetables and certain
oncotherapies. One can balance this against the very
real potential for other beneficial activities of garlic
and Allium components on health, and on cancer, but we
don't know how the balance of benefit / harm will swing,
hence our own cautionary stance.
Brassica / Cruciferous Vegetables
-- Safety of
One final issue on components of brassica vegetables
concerns the component sulforaphane: as Zhou et al.213
observe, this biologically active phytochemical found
abundantly in broccoli, can significantly down-regulate
cytochrome P450 3A4 (CYP3A4) expression in human primary
hepatocytes, and although this mechanism serves as part
of the foundation for its anticancer and chemopreventive
activity, there may be some potential for
adverse interaction with CYP3A4-mediated agents such as
exemestane (Aromasin), and we await clinical studies to
determine whether such interaction exerts clinically
significant impact on concurrent administration (see
also Maheo et al.214
who first reported the CYP3A4 enzyme operation in
And the review of Paolini & Nestle215
found that "cruciferous isothiocyanates such as
sulforaphane, most often considered as beneficial
phase-II detoxifying system inducers, turn out to be
genotoxics or strong promoters of urinary bladder and
liver carcinogenesis as well as inducing cell cycle
arrest and apoptosis".
an isothiocyanate (isothiocyanates being the family of
compounds found in large amounts in cruciferous
vegetables in the form of the thioglucoside precursors
(glucosinolates)) that has been isolated from SAGA
broccoli as the major phase II enzyme inducer present in
organic solvent extracts of this vegetable. The
(chemo)protective effect of sulforaphane, an
isothiocyanate - - which is liberated from glucoraphanin
(GRP), its glucosinolate precursor, by myrosinase
hydrolysis, is believed to involve the induction of
Phase-II metabolizing enzymes which are active in the
detoxification of many carcinogens and ROS (reactive
oxygen species), and by this protecting cells against
DNA damage and subsequent malignant transformation.
However, as discovered by Paolini et al.216:
(1) in some cases these enzymes also bioactivate several
hazardous chemicals, and (2) that despite sulforaphane's
projected benefits, overlooked is its unknown effects on
the Phase-I enzyme systems involved in the bioactivation
of a variety of carcinogens, where not only has
sulforaphane been shown to inhibit the CYP2E1 cytochrome
P-450 enzyme involved in the activation of a variety of
carcinogen, but also to down-regulate CYP3A4 expression
(as shown by the separate Zhou and Maheo studies, cited
above), and this raises issues of potential significant
and possibly adverse interaction with CYP3A4-mediated
oncotherapy agents such as endocrine agent exemestane
(Aromasin), taxanes (docetaxel (Taxotere), paclitaxel
(Taxol)), and nab-paclitaxel (Abraxane) or any of the
Vinca alkaloids (vinorelbine (Navelbine), vinblastine
(Velban), vincristine (Oncovin)), and the platinum agent
carboplatin (Paraplatin), suggesting caution of
coadministration of high-sulforaphane-content dietary or
supplemental sources with any of the CYP3A4-dependent
classes of oncotherapy just notes, until further in vivo
or ideally human clinically studies can demonstrate
compellingly the safety ands non-problematic nature of
this, there is another disturbing aspect of
sulforaphane’s induction of Phase-I CYP bioactivating
enzymes: sulforaphane is as we noted above liberated
from its glucosinolate precursor glucoraphanin (GRP),
and there is some evidence that GRP may possess
co-carcinogenic properties. Indeed, by inducing Phase-I
CYP bioactivating enzymes, GRP may trigger the
conversion of benzo[a]pyrene to carcinogenic reactive
intermediates like diol-epoxides, and recent studies
have shown that a cruciferae-based diet containing a
selection of brassicaceous vegetable that includes
broccoli, Brussels sprouts or cauliflower, leads to a
significant increase in Phase-I enzymes such as
CYP1A1/2, which can bioactivate PAHs, dioxins, aromatic
amines and nitrosamines (as reported by Paolini et al.216,
and priorly confirmed as well in the study by Vistisen
who found that in nine healthy volunteers daily
ingestion of 500 g of broccoli for 10 days increased the
CYP1A2 ratio adversely by an average of 12% compared to
a comparable diet of non-cruciferous green vegetable,
see also Lampe et al.218.
impact of the brassica diet not only hinges on adverse
interactions across CYP3A4 as documented extensively in
this review, but also on CYP1A2 activity and is
increased by cigarette smoke, well-cooked meat, and
unfortunately by cruciferous vegetables and this is
adverse, since CYP1A2 metabolizes various environmental
procarcinogens, such as heterocyclic amines (HCAs),
nitrosamines and aflatoxin B1, in keeping with the
research of Lampe et al.218,
where it was found that that under controlled dietary
conditions, at moderate levels of intake (428 g),
brassica vegetables increased (while apiaceous
vegetables decreased, and allium vegetables did not
change) CYP1A2 activity by 18 - 37%, when compared with
a basal, vegetable-free diet.
-- Brassica / Cruciferous Vegetables - I3C, DIM
studies provide evidence that the consumption of
cruciferous vegetables protects against cancer more
effectively than the total intake of fruits and
vegetables. The indole-3-carbinol (I3C) component in
brassica and cruciferous vegetables may also be
protective in cervical and possibly prostate cancers,
probably by enhancing 2-hydroxyestrone (an estrogen
receptor antagonist - non-stimulative of breast tumors -
produced in estrogen breakdown) at the expense of
16-hydroxylation (an estrogen receptor agonist -
promoting breast tumors - also produced in estrogen
breakdown), thus shifting the ratio to the favorable
estrogen breakdown product219.
Epidemiological, laboratory, animal and translational
studies increasingly indicate that dietary
indole-3-carbinol (I3C) prevents the development of
estrogen-enhanced cancers including breast, endometrial
and cervical cancers220,221,222.
However, there are significant concerns surrounding the
issue of potential adverse interactions through the P450
cytochrome family of enzymes, especially on the hepatic
microsomal metabolism of tamoxifen (TAM): so Daniel
Parkin and Danuta Malejka-Giganti223
at the University of Minnesota in another in vivo study
found that although metabolism of TAM was unaffected by
DIM, formation of N-desmethyl-TAM was increased 3-fold
by I3C, and since N-desmethyl-TAM is transformed to a
genotoxic metabolite, this appears to suggest that
dietary exposure to I3C may enhance hepatic
carcinogenicity of TAM in the rat.
again, conflicting results exists: so Dustin Leibelt and
at Oregon State University failed to detect any direct
toxicity by long-term exposure to I3C and DIM, even at
doses up to approximately 5–7 times the daily dose
recommended by commercial suppliers of I3C supplements,
and at exposure 10 times higher than the current human
dose for DIM, and the researchers concluded that data
from their present study confirms results from
short-term studies indicating that both I3C and DIM are
relatively nontoxic compounds, and furthermore confirm
earlier long-term feeding studies in other models,
including the rainbow trout and the same strain of rat
used in the present study, that I3C is not a complete
carcinogen, a finding also confirmed by Gary Stoner and
who nonetheless warn that I3C may not an appropriate
chemoprotective agent for human use in that it appears
to both inhibit (breast, colon) and promote (liver)
carcinogenesis. And the Leibelt study warns of two
distinct concerns: (1) that the prolonged use of I3C for
cancer chemoprevention exhibits a potential for
promotion of liver neoplasms, although they prudently
admit that the long-term post-initiation effects of I3C
in hepatocarcinogenesis are not consistent across
species (trout, rats, black mice), leaving open what the
real risk is, if any, in the human context; and (2) the
induction of CYP enzymes by I3C, especially those of the
1A subfamily, could be a cause for concern, as these
play a role in activation of polycyclic aromatic
hydrocarbons (PAH) and aromatic amines with known
toxicities, a concern that appears not to be shared with
DIM. The reason for this may be that in the acidic
conditions of the stomach after oral exposure, I3C
becomes a complex mixture more than 20 different
I3C-derived compounds, including DIM, all having various
pharmacological/toxicological effects, while DIM is
relatively more stable in acid and does not robustly
undergo further condensation reactions, suggesting that
the more stable DIM component may be the safer compound
to deploy in the human context.
yielded dose-dependent increases in the hepatic P450
level according to the research of Malejka-Giganti and
at the University of Minnesota who in their animal study
of female Sprague-Dawley rats tested 5, 25 and 250 mg/kg
body weight of I3C and DIM at 8.4 and 42 mg/kg body
weight, finding that oral intake of I3C or DIM at lower
dose levels did not alter CYP-mediated metabolism of
tamoxifen, and hence, would not alter its therapeutic
efficacy. Since for a human female weighing 140 lbs,
equivalent to about 64 kilograms (kg), the CYP-mediated
TAM metabolism altering dose (250/mg/kg) would map to
16,000 mg, which is easily 40 times greater than the
recommended I3C dosing of 400mg/daily, and from these
findings it would appear that doses up to 1600mg/daily
would be without adverse interactions on tamoxifen
metabolism and efficacy, assuming the same 140 lbs
female, and that 400mg/daily IC3 ingestion is at a level
to assure no oncotherapy interference with tamoxifen -
but given conflicting findings in the evidence
base, this can be no means be considered dispositive.
Thus, we note the
conclusions of a comprehensive review by EG Rogan227
with the Eppley Institute for Research in Cancer and
Allied Diseases at the University of Nebraska Medical
Center who notes that
"although I3C has
been shown to protect against tumor induction by some
carcinogens, it has also been observed to promote tumor
development in animal models"
and that in humans, concerns have been raised that I3C
might increase the formation of estrogen metabolites
that induce or promote cancer". In this connection, the
in vivo component of I3C, 3,3'-diindolylmethane (DIM) is
unlike, its precursor, I3C itself, not highly
enzyme-inducing, where it appears from the evidence base
that it is the unwanted enzyme induction by I3C that
accounts for any perceived adverse tumor promotion
activity by I3C, and lacking these unwanted
enzyme-inducing effects, DIM, which appears to share the
positive efficacy of I3C in breast and cervical
carcinomas, would be suggested as the safer compound in
human use (and in keeping with the conclusion of
Leibelt, cited above, that
exposure to DIM produced no observable toxicity, and
comparison to I3C indicates that DIM is a markedly less
efficacious inducer of CYP in the rat at doses relevant
to human supplementation").
-- Further Evidence of CYP-mediated Potential Harm of
Brassica / Cruciferous Components
animal studies have strongly suggested promotion of
endometrial adenocarcinoma by I3C which appears to be
correlated with the induction of CYP1A and CYP1B enzymes
and sequential formation of toxic estradiol catechol
metabolites, suggesting AhR-mediated pathways may be
and with respect to DIM, in vitro studies have shown it
to exhibit estrogenic activity in certain cancer cells,
via ligand-independent activation of ER229,230,231.
In addition, it
that regular administration of the glucosinolate
precursor glucoraphanin (GRP) by myrosinase hydrolysis
actually increases rather than decreases cancer risk,
especially for individuals exposed to mutagens and
carcinogens in the environment (e.g., tobacco smoke, and
other certain industrial exposures), via phase-II
metabolizing enzymes which, although generally have been
taken as beneficial, can bioactivate several hazardous
chemicals. And we are nonetheless left with unknown
effects of brassica / cruciferous even on phase-I enzyme
systems involved in the bioactivation of a variety of
carcinogens, which induce phase-I carcinogen-activating
enzymes including activators of carcinogenic PAHs
(polycyclic aromatic hydrocarbons), and concurrently
with this phase-I induction GRP over-generates reactive
oxygen species (ROS) while also facilitating the
metabolic activation of the PAH benzo[a]pyrene to
reactive carcinogenic forms, along with observed
DNA-damaging genotoxicity. And these adverse effects
were seen at dietary-realistic levels, as Moreno Paolini
at the University of Bologna and coresearchers (see
previous) have demonstrated: despite glucosinolate
content in brassica / cruciferous vegetables varying
with species, cultivation, and the parts of the plant
used, the mean content was 100 mmol/100 g fresh weight
(a typical portion of vegetables), corresponding to 26
mg GRP (55% of the total), which was sufficient to
induce a powerful and highly significant increase (from
4.4 to 13-fold) of several phase-I
carcinogen-metabolizing enzymes following a single or
repeated treatments of GRP, with a significant increase
in CYP1A1/2 enzymes which activate polychlorinated
biphenyls, aromatic amines and PAHs, CYP3A1/2 enzymes
activating nitropyrenes, aflatoxins and PAHs, CYP2B1/2
enzymes activating olefins and halogenated hydrocarbons)
and CYP2C11 enzymes activating nitrosamines, aflatoxins
and ochratoxins, all of which led the researchers to
"The observed CYP
induction following GRP administration suggests that GRP
may possess co-carcinogenic properties"216
(see also Lampe et al.218).
This brassica / cruciferous components like GRP may
instead of behaving chemopreventively, in fact exert
adverse toxicological effects via the induction of
carcinogen-bioactivating enzymes, and via generating
oxidative stress and genotoxic DNA damage, of especial
concern for individuals exposed to mutagens and
carcinogens known to be metabolized by phase-I
bioactivating enzymes, include of course cancer patients
who have have impaired DNA repair mechanisms (also in
agreement with Paolini & Nestle215.
for harm comes from a wholly different mechanism -
researcher Jacques Riby and colleagues at the Division
of Nutritional Sciences and Toxicology of University of
California, Berkeley found that DIM
(3,3′-Diindolylmethane) - a major in vivo product of
acid-catalyzed oligomerization of I3C
(indole-3-carbinol) present in brassica vegetables like
broccoli and others in the genus - is a
promoter-specific activator of estrogen receptor (ER)
function in the absence of (17β-)estradiol, inducing
proliferation of these cells in the absence of steroid,
suggesting promoter-specific, ligand-independent
activation of ER signaling by DIM, functioning as
therefore a selective activator of ER function232.
-- Warning: Insufficiency of Myrosinase Inactivation of
Dietary Brassica / Cruciferous Components
It is often cited
in defense of the safety of brassica / cruciferous
consumption concurrently with various oncotherapies
whose metabolism is CYP-mediated across the same p450
CYP enzymes that are influenced by brassica /
cruciferous vegetables, that cooking can inactivate
myrosinase, the enzyme which hydrolyzes glucosinolates
in cruciferous and brassica vegetables into biologically
active isothiocyanates (ITC). However, the fallacy here
is the failure to realize, well-documented, that even if
myrosinase has been inactivated, intestinal microbial
metabolism of glucosinolates also contributes to ITC
as colon microflora appear to be able to catalyze
glucosinolate hydrolysis when vegetables are cooked, so
that isothiocyanates still arise despite cooking, and
although this is apparently at a lower level (10% to
20%), there is absolutely no reassuring data to show
that such activation by bacterial myrosinase isn't
sufficient to support adverse interaction with active
oncotherapy. It isn't just the range of methods used to
prepare these foods and the associated degree of
myrosinase inactivation that determines potential
adverse interaction, but also the activity level of the
consumers’ dentition / chewing, as well as the
consumer's colonic microbes, that all contribute to an
individual's risk exposure, and indeed this is also
dependent on genetic polymorphisms in biotransformation
enzymes that metabolize ITC, and possibly as well
receptors and transcription factors that interact with
these compounds, all factors independent of cooking
inactivation and contributing wide individual variation
which may sustain adverse risk at clinically significant
levels in any one individual (on bacterial glucosinolate
metabolism occurring in the digestive tract and the
modulate of the process of glucosinolate metabolism in
relation to the composition and activity of the colon
microflora, see Krul et al.234).
And direct evidence of colonic hydrolysis of
glucosinolates in human subjects themselves has been
provided in a study by Serkadis Getahun and Fung-Lung
with the American Health Foundation which documented a
linear increase in the formation of isothiocyanates for
2 hours after incubating with bowel microflora cooked
watercress containing glucosinolates but no plant
And as Lilli Link
at Columbia and John Potter at the Fred Hutchinson
Cancer Research Center have noted, the average excretion
of isothiocyanates in the 24-hour urine collection was
still a non-trivial 20.6 µmol even in human subjects who
ate broccoli steamed for 15 minutes237,
confirmed also in the earlier research of Clifford
Conaway's team at the American Health Foundation236),
and this independent of possibly further enhancement of
level under variable circumstances of the additional
affecting factors such as gut microflora, pH and the
presence of various cofactors. Furthermore,
glucosinolate hydrolysis in the gut can produce a range
of breakdown products in addition to the
isothiocyanates, and the yields of such different groups
of metabolites, including isothiocyanates, nitriles and
epithioalkane nitriles, and the factors that may affect
these yields after glucosinolate ingestion, are not well
understood, but the delayed release of isothiocyanates
in significant quantities after cooking - which
supposedly should have inactivated such production - has
been decisively demonstrated recently by Gabrielle
at Aberdeen, via the action of the colon microflora when
dietary glucosinolates reached the colon, and such
colonic hydrolysis - as opposed to and in addition to
myrosinase-mediated hydrolysis - of glucosinolates may
yield other active products such as nitriles in addition
to isothiocyanates. Finally, it has been shown by Fekadu
Kassie's team in Vienna collaborating with the UK
Institute of Food Research that juices of Brussels
sprouts, white and green cabbage, cauliflower, kohlrabi,
broccoli, turnip, and black radish all induce
pro-mutagenic genotoxic activity239.
Another fallacy should also be noted here: not all
brassica / cruciferous vegetables are created equal:
although heating to 70 °C and above decreased the
formation of both sulforaphane and sulforaphane nitrile
products in broccoli florets, this was not true of
broccoli sprouts, whose sulforaphane content was
unaffected by such heating240,
and compared to boiling, cooking by steaming,
microwaving and stir-fry did not produce significant
loss of glucosinolates the content of the 7 major
glucosinolates in broccoli, Brussels sprouts,
cauliflower and green cabbage241,242,243.
The prudent and
cautionary advice of Gary Stoner at Ohio State
University is therefore worth remembering:
the exception of the studies cited in this report
(6,22,23), no other attempts have been made to weigh
chemoprotective benefits against promotional risk for
I-3-C. In spite of the hope that I-3-C might be a
non-genotoxic alternative for tamoxifen or synergin for
adjuvant therapy, the risk of promoting colon and liver
cancer, especially if I-3-C is used as a `health food'
by the presumably disease-free general public is unwise
and potentially dangerous"225.
Similarly, Roderick Dashwood at the University of Hawaii
who notes that some studies
evidence for promotion or enhancement of carcinogenesis,
depending upon the initiator, exposure protocol and
species. In the absence of detailed information on the
inhibitory and in particular, promotional mechanisms, it
would seem advisable to proceed with caution before
including I3C in extensive human clinical trials"244.
Adverse Food-Oncotherapy Interactions, Known To Date
The major food
items with some evidence of potentially adverse
interaction during concomitant oncotherapy across the
hepatic enzyme system
choi, broccoli, brussel sprouts, cabbage,
cauliflower, collards, daikon, horseradish, kale,
kohlrabi, mizuna, mustard greens, napa (or Chinese)
cabbage, radish, rutabaga, tatsoi, turnips, wasabi,
powder remains unproblematic if and only if used not
at food-item-levels but at light seasoning-levels
(no more than a sprinkling or "small pinch")
the juice and
fruit of grapefruit and seville oranges;
the juices of
wild grape, pomegranate, and black raspberry (and
probably others not yet tested);
teas of licorice, goldenseal and chamomile;
primrose oil (EPO) and borage oil;
sage, thyme, and cloves
(which like garlic powder, remain unproblematic if
and only if used at light seasoning-levels)
findings subject to change and refinement under
Against this adverse impact of brassica vegetables,
Breast Cancer Prevention Watch finds intriguing the fact
that apiaceous vegetables (carrots, parsnips, celery,
dill and parsley) decreased mean CYP1A2 activity by
~13–25%, which suggest to us - but note without any
clinical data to support the hypothesis - that the
differential CYP1A2 response to the brassica and
apiaceous vegetable diets
be leveraged to in largely past cancel out or nullify
the adverse CYP1A2 impact of the brassica components by
co-consumption with apiaceous vegetables.
Dosing and Meal-based High-Fat Consumption
Given all the negative press on the potential adverse
interactions CYP3A4-metabolized drugs and CYP3A4
inhibitors or inducers, we have recently encountered a
new twist on the theme, the suggestion that such
interaction could be leveraged positively, even to
economic advantage. So Allison Grandley, writing for
Medscape Medical News, quote University of Chicago
oncologists Mark Ratain and Ezra Cohen245
to the effect that "Simply
by changing the timing — taking this medication with a
meal instead of on an empty stomach — we could
potentially use 40% or even less of the drug" and that
"Since lapatinib costs about $2900 a month, this could
save each patient $1740 or more a month"246.
Colleague and co-author Dr. Cohen continues with faint
caution, suggesting that "Dozens,
if not hundreds, of drugs should be studied in this way,
the authors suggest. "If we understood the relationship
between, say, grapefruit juice and common drugs, such as
the statins, which are taken daily by millions of people
to prevent heart disease, we could save a fortune in
We would strongly advise against any such suggestion,
and in fact - apparently unknown to writer Allison
Grandley - the authors of the study, Marc Retain and
Ezra Cohen of the University of Chicago, do NOT in fact
themselves advise taking lapatinib at reduced dose with
a meal, despite their soaring rhetoric to the media;
they state clearly in their article that they "do
not recommend off-label administration of lapatinib
outside of a clinical trial"246,
and to do otherwise would of course have grave
medico-legal implications for the authors, as despite
the appearance to the contrary there is not one iota of
clinical data to suggest the safety and efficacy of any
mode of administration of lapatinib other than the
sanctioned fasting mode, nor for the safety and efficacy
of lapatinib at any dose reduction from the sanctioned
schedule, whether with or without food. Meal-based dose
reduction may potentially compromise the treatment
benefit of an effective therapy for advanced or
metastatic breast cancer: fasting conditions are, by
definition, reproducible, whereas taking a meal (along
with a long-term drug administration by oral route) is
not replicable and an obvious source of heterogeneity in
terms of inter-patient and/or intra-patient
pharmacokinetic variability. The risk of taking
lapatinib with food (no matter if standardized or not)
is to generate grossly unpredictable plasma
concentrations and to consequently worsen efficacy
and/or adverse effects. The pharmacokinetic data on
lapatinib clearly indicate that decreasing the dose and
using the contents of a meal to adjust bioavailability
in order to achieve therapeutic plasma concentrations is
not only unreliable but potentially highly dangerous.
Dietary manipulations with inconsistent effect on drug
exposure are to be avoided in clinical use, as the
clinical benefit of such maneuvers unknown and
potentially of significant harm to patients via
compromising a drug's efficacy or toxicity.
Furthermore, it should be noted that the Dartmouth study
by Nandi Reddy247
that Marc Retain and Ezra Cohen of the University of
Chicago cite as support is a phase I open label
pharmacokinetic study that suggests that full dose, not
reduced dose, lapatinib exposure is significantly
increased when taken with a high-fat meal as compared
with a fasted state; the authors of this article did not
study the exposure from a lower dose of lapatinib (250
or 500 mg) taken with a meal compared to the 1,250-mg
dose taken 1 hour before or after meals, and so such
exposure is unknown, and hence this study is wholly
insufficient to found any conclusion about reduced-dose
lapatinib, such a conclusion requiring further clinical
studies including a relative bioavailability study
evaluating lower lapatinib dose taken with a meal versus
a 1,250-mg dose taken without a meal. Overlooked by
Retain and Cohen are both inter- and intra-patient
variability in bioavailability, along with dietary
effects on concomitant medications, and differing
patterns of oral intake and food constituents.
Individual food intake varies from time to time, and the
meal's composition (caloric intake and fat, protein, and
carbohydrate content) can have erratic and unpredictable
effects on gastric emptying and intestinal motility in
any given individual, resulting in no reliably assured
drug level. Indeed, FDA submitted preapproval clinical
studies examined the average increase in lapatinib's
bioavailability with a low-fat and a high-fat meal, and
found that individual patients taking the recommended
dose with food will have highly variable (52%
coefficient of variability) and unpredictable changes in
Data presented by Nandi Reddy of Dartmouth Hitchcock
Medical Center during the ASCPT meeting (see above)
showed that this food effect showed broad variability
between individual patients, with 48% inter-patient
variability in apparent oral clearance, yielding 68%
variability in AUC systemic exposure (area under the
curve). However, this still underrepresents the
magnitude of variability experienced across individual
study, sometimes dramatic in range, from a slight
decrease to as high as a 24-fold increase, and as Kevin
Koch and GlaxoSmithKline (GSK) coresearchers249
have observed, participants in the controlled studies
ate precisely identical meals at the same time and
consistently each day as required by the protocol, an
artificial scenario rarely if ever seen in the real
world. Unfolding in such eating pattern variations may
countervail proposed cost savings by increased toxicity
or unfortunate disease progression if appetite were
sufficiently depressed or inter-patient variability
dealt some unlucky patient a suboptimal plasma level of
And as noted by Atiqur Rahman with CDER at the FDA (see
Rahman et al., above), the AUC ratios (fed/fasted ratio)
could range from less than one for some individuals to
as high as 24-fold increased exposure if accompanying a
high-fat meal, translating to the scenarios of some
patients being under-dosed while others being massively
and dangerously overdosed from the mean-adjusted dose of
lapatinib. This is especially serious given the QT
prolongation potential of lapatinib, as found in a dose
escalation study in patients with advanced cancer which
observed a relationship between lapatinib concentration
and the QT interval, so that high concentration induced
artificially by food consumption and food content
manipulation could led to highly adverse cardiac events
such as cardiac rhythm disturbances including fatal
cardiac dysrhythmias like torsades de pointes250.
The US FDA Clinical Pharmacology and Biopharmaceutics
documents lapatinib-induced QT prolongation, noting that
administration of lapatinib with food
expected to further prolong the QTc interval"
a risk factor for torsades de pointes and/or sudden
The authors Ratain and Cohen even less prudently offer a
suggestion that even greater cost savings might be
achieved by drinking grapefruit juice with food to
further boost bioavailability, this despite the large
body of literature demonstrating the highly variable
effect of grapefruit juice with bioavailability being
modulated in either direction due to multiple effects on
metabolic enzymes including the hepatic p450 cytochrome
system, and intestinal and hepatic drug transport
proteins (see Koch et al., above)), with well-documented
adverse consequences, possibly also increasing the risk
of serious toxicity from other drugs prescribed
concomitantly. We simply do not want to add to the
erratic and generally adverse interactions from
furanocoumarins like the bergamottin component of
grapefruit juice. To offer a final cautionary scenario:
a patient, following the Retain-Cohen suggestion,
consumes reduced dose (250 - 500mg) of lapatinib with a
high-fat meal, but for this patient - and possibly for
this meal among many others - the predominant fat
contribution comes from soy-based fat via soybean, which
would in turn deliver high daidzein and genistein
isoflavone soy components. But these soy components are
CYP3A4-mediated in metabolism -and, unfortunately,
lapatinib metabolism, and hence both its safety and
efficacy, is also severely CYP3A4-mediated, therefore
leading to potential highly adverse drug-food
interaction over the p450 hepatic cytochrome enzyme
system. In any rational and moral approach to drug
administration, we cannot accept that some patients get
unlucky by virtue of meal composition. In a fasting
state, all patients are created equal.
A Plea for
The TAM-SSRI Lesson
developments support our cautionary stance: the results
by SK Knox and coresearchers252
reported at the June 2006 ASCO meeting found that in
patients that coadminister tamoxifen and an
CYP2D6-inhibitory agent such as an SSRI or other
inhibitory agent (fluoxetine (Prozac), paroxetine
(Paxil), sertraline (Zoloft), cimetidine(Tagamet),
amiodarone (Cardarone), doxepin (Adapin/Sinnequan),
ticlopidine (Ticlid) and haloperidol (Haldol) were
tested), had significantly worse time to recurrence
(TTR) and disease free survival (DFS), in the real human
clinical setting, and a large body of robust RCTs,
systematic reviews, and meta-analyses such as the recent
(May 2013) meta-analysis of Zhiyu Zeng and colleagues253
reviewing 20 eligible studies on tamoxifen and CYP2D6
polymorphisms (n=11,701) found that CYP2D6 polymorphisms
may influence tamoxifen treatment outcomes as to
disease-free survival (DFS) in breast cancer patients.
But that puts
many oncologists in the embarrassing position of having
countenanced significant adverse impact on patient
outcome on the basis of an optimistic stance that, after
all, only the potential for harm had priorly been
demonstrated, not actual harm; with the Knox findings we
now know retrospectively that the potential was real and
did translate into adverse impact of patient outcome in
terms of both disease recurrence and survival, and so
this seriously degrades the value of any optimistic
stance on these matters.
stance most oncologists took on the above issue - of the
potential compromise in the antitumor efficacy of
tamoxifen by concomitant administration of SSRI
antidepressants - was not only inconsistent, but would
appear hypocritical, as the attitude was "the jury is
still out" so co-administration should continue.
Yet as to
comparable potential adverse interactions between
oncotherapeutic agents and various agents, the vast
amount of which was based solely on in vitro, not in
vivo or human clinical data, oncologists typically argue
strongly that against co-administration, regardless of
here too "the jury being out" (and after all, we have a
perfectly good solution to the TAM-SSRI interaction
problem: use a NSRI such as the highly effective
antidepressant (and hot flash relief) venlafaxine
Lack of Robust Evidence of Harm
oncologists typically argue strongly against
co-administration of antioxidants and oncotherapeutic
agents, yet on the balance of the evidence, the
preponderance of data suggests a synergistic or at least
harmless effect with most high-dose dietary antioxidants
and chemotherapy, and claims to the contrary are
inconsistent and not supported by the evidence data, in
that if antioxidants were in reality a significant
threat to the efficacy of standard CT and RT,
antioxidant-rich foods like fruits and vegetables would
also be prohibited during therapy, but no rational
oncologist would make such a recommendation (in part
because studies have supported the positive benefit of
such consumption to overall health and QOL (quality of
there is again an inconsistency and evidence-based
research, and our own review, has already challenged
this inconsistency from another more critical vantage
point: synthetic antioxidants are already in wide-scale
use by both medical and radiation oncologists to control
the adverse effects of cytotoxic CT treatments. There
are several radioprotectant and chemoprotectant agents
that are widely used in conventional oncology whose
principal mode of activity is antioxidative such as the
highly effective and successful
used as a radio-protective and cytoprotective,
a bladder-cytoprotective, dexrazoxane (Zinecard) a
cardioprotective against oncotherapy cardiotoxicity, and
a radioprotective used to treat RIF, radiation-induced
fibrosis, all antioxidants. The research on metastatic
breast cancer of Keith Block254
at the Center for Integrative Cancer Care and University
of Illinois, among many others, suggest that patients
who received chemotherapy with antioxidant support at
their clinic had better outcomes rather than the
non-observed interference by antioxidants of
conventional CT therapies. This raises a consistency
problem for any oncologist who argues that antioxidants
should not be co-administered with oncotherapies, but it
would appear that comparable conventional antioxidants
(all FDA approved for use for their benefits via their
antioxidant activity) are coadministered and apparently
without adverse interaction or interference. For
example, amifostine, a pharmacological antioxidant used
as a cytoprotectant (protecting normal tissues relative
to tumor tissue - that is, both as a
chemoprotectant and as a radioprotectant - was reviewed
and found to exert protection against mucositis,
esophagitis, neuropathy (but not against
cisplatin-induced ototoxicity), with no evidence of
tumor protection observed255.
Keith Block at
the Institute for Integrative Cancer Research and
Education and coresearchers recently conducted a
of 19 RCTs on the efficacy of coadministration of
antioxidant supplementation with chemotherapy evaluating
Vitamin A, Vitamin C, Vitamin E, melatonin, NAC, ellagic
acid, glutathione, and an antioxidant mixture in
subjects with predominantly advanced or relapsed
disease. They found that none of the trials found any
evidence of significant decreases in efficacy from
antioxidant supplementation concurrent with
chemotherapy, with many of the studies finding that
antioxidant supplementation yielded either increased
survival times, increased tumor responses, or both, as
well as fewer toxicities than controls, although they
note that lack of adequate statistical power was a
consistent limitation, so that large, well-designed
studies of antioxidant supplementation concurrent with
chemotherapy are further warranted. See also the review
of Moss who concluded that "A
blanket rejection of the concurrent use of antioxidants
with chemotherapy is not justified by the preponderance
of evidence at this time"257,
and similarly for radiotherapy, concluding that
preponderance of evidence supports a provisional
conclusion that dietary antioxidants do not conflict
with the use of radiotherapy in the treatment of a wide
variety of cancers and may significantly mitigate the
adverse effects of that treatment"258.
This is cross-confirmed in other reviews259,260
which concluded from their review (since the
1970's) of 280 peer-reviewed in vitro and in vivo
studies, including 50 human studies involving 8,521
patients, 5,081 of whom were given nutrients, that this
comprehensive evidence base consistently shows that
not interfere with therapeutic modalities for cancer",
and that furthermore, it appears that "non-prescription
antioxidants and other nutrients enhance the killing of
therapeutic modalities for cancer, decrease their side
effects, and protect normal tissue",
with 15 human studies of 3,738 patients actually
suggesting increased survival.
The subtle and complex issue involved in this arena are
demonstrated by the exchange between Brian Lawenda at
the Naval Medical Center San Diego and Jeffrey Blumberg
at Tufts on the one hand, as per their JNCI article261,
and their several respondents. Finally, with respect to
the Lawenda JNCI article, it should be noted that (1) it
ignores the two reanalyses and reinterpretations of the
seemingly negative Bairati study which in fact shows no
harm to coadministration of antioxidants and radiation
therapy except for patients who also smoke during
therapy (see immediately below for full discussion), and
(2) the Lawenda article actually found that antioxidants
may enhance the effects of chemotherapy as well as
diminish its toxicity ("no
decrements in tumor response rates or survival rates
they conclude) yet the study abstract counterfactually
states that supplemental antioxidants should be
discouraged during both chemotherapy and radiation, in
contradiction of their own conclusions within the
article itself, especially regrettably since virtually
all popular media solely read the abstract not the full
paper, as did many health professionals themselves,
hence leading to a trumpeting of an injunction against
coadministration of antioxidants and oncotherapy (chemo
and radiation therapy) not supported by the evidence
(like the somewhat hysterical and wholly erroneous
headline from Randy Dotinga in HeathDay: "Cancer
Patients Should Steer Clear of Antioxidants Research -
review suggests they may help cancer cells resist chemo,
We have often remarked on the dangers of lay
misinterpretation of complex medical research findings,
and of lay and professional reading of only article
abstracts not the full text, and moreover doing so
uncritically, without the skills for methodological
appraisal, and this adds another case in point.
Much of the
motivation for a prohibition against coadministration of
antioxidants with radiation therapy comes the widely
cited study of such coadministration in head and neck
cancer patients conducted by Isabella Bairati and
which gave (synthetic) alpha-tocopherol and
beta-carotene supplements to patients at high risk of
second primary cancers. Higher rates of second
primary cancers, along with more recurrences, were found
in the supplementation group, with higher all-cause
mortality and a trend towards higher cancer-specific
mortality during supplementation. These negative
findings were disseminated and cited widely in the
professional literature and in the popular media, and to
this day account for much of the common and pervasive
belief in the oncology and radiology communities that
antioxidant coadministration with chemotherapy or
radiotherapy must be avoided as such practice may lead,
as per the study results, to actual harm and effect
Unfortunately, what the professional communities and the
lay public failed to realize - even to this day - was
that the findings are in fact in error: analysis
of Bairati’s study population by Francois Meyer at Laval
University and coresearchers263
established that the observed excess recurrences were
restricted to only those patients on supplementation who
continued to smoke throughout radiation therapy,
suggesting that the efficacy of radiation therapy was
reduced only by the combined exposures, since for
nonsmokers receiving supplements, the hazard ratios
hovered near one so that there no was excess risk of
mortality compared to the placebo group and hence no
adverse effect of supplementation. Thus patients
who either do not smoke or quit smoking during therapy
may accrue the benefits of antioxidant supplementation
for the reduction of side effects, and without affecting
therapeutic efficacy of the radiation therapy.
The same team of researchers undertook another
of the Bairati study which found, against the putative
negative interpretation of the study, that those
patients with the highest dietary intake of
beta-carotene actually had significantly fewer radiation
side effects, and that furthermore those patients with
the highest plasma levels of beta-carotene also had a
33% reduction in local recurrences, clearly not only not
adversely affecting therapeutic efficacy of the
radiation therapy, but also providing improved outcome
via recurrence reduction. When the antioxidant was
allowed to do its work without the ill effects of
tobacco, its ability to reduce side effects without
affecting therapeutic efficacy was shown. Thus, a
leading study put forth to suggest that antioxidants
provide a protective shield to tumors during radiation
therapy is found (in the absence of concurrent smoking)
to actually establish no such thing, but rather to
suggest that coadministered antioxidants and
radiotherapy not only protect patients from
therapy-induced side effects, but also benefit outcome
by reduction of recurrence (also concluded by numerous
other studies, including the recent review of Paul
Okunieff and colleagues265
at the University of Rochester Medical Center).
A more recent
(2008) systematic review266
examined 33 RCTs on the effect of concurrent antioxidant
supplementation on chemotherapeutic toxicity evaluated
Vitamin A, Vitamin E, melatonin, NAC, ellagic acid,
glutathione, L-carnitine, selenium, CoQ10, and an
antioxidant mixture in subjects with predominantly
advanced or relapsed disease. It found that the majority
(24) of the studies demonstrated evidence of decreased
toxicities from antioxidant-chemotherapy
coadministration, nine studies reported no difference in
toxicities, with only 1 study on Vitamin A reporting a
significant increase in toxicity in the antioxidant
group. In addition several (5) studies found that the
antioxidant group completed more full doses of
chemotherapy or had less-dose reduction than control
groups. And although statistical power and poor study
quality were concerns with some studies, the authors
concluded that there is evidence
antioxidant-chemotherapy coadministration holds
potential for reducing dose-limiting toxicities, and
without affecting therapeutic efficacy of the therapy.
In sum, just as there can be no blanket disjunction
against all coadministration during chemotherapy or
radiation therapy, neither however can there be a
blanket inclusion, and each CAM agent and intervention
must be critically assessed, as witnessed are detailed
coverage above of several specific natural agents that
require caution against coadministration by virtue of
potentially adverse interactions with oncotherapies.
Science: The Strange Case of Warfarin
Joanna Marino and
reviewed the literature on warfarin and supplement
interactions, finding wide variability in the quality or
reports and noting that the high preponderance of the
data on this issue was derived from case reports or from
an extrapolation from supplement mechanisms of action
that would suggest such potential interaction, but that
the strength of evidence was lacking for the majority of
the herbal products reviewed, making firm conclusions
But we have data
that suggests that potential adverse interactions
between warfarin and CAM agents have been overemphasized
and may in fact be of limited clinical relevance. First
in a retrospective cohort study of CAM agents and
warfarin in matched control (246 warfarin and 246
control group patients), Munad Khan and colleagues269
at the University of Melbourne found that in the
warfarin group, CAM users and non-users reported a
similar number of events below and above their
therapeutic INR range and when the INR exceeded a
reading of 5. CAM users exhibited a similar number of
clotting events (9% vs 10%) compared to CAM non-users in
the warfarin group, and although they tended to have
more abnormal bleeding events (42% vs 30% than CAM
non-users, these events were uncommon and the finding
may have occurred by chance as the authors candidly
acknowledge. Second Vivian Leung and colleagues271
at the University of British Columbia conducted a cohort
study of the effects of CAM usage concurrent with
warfarin, finding that there was no significant
difference in CAM use or consumption of vitamin K-rich
foods between patients with and without INRs greater
than 4 or for patients with and without INRs less than
2, and that exposure to CAM was not associated with an
increase in the risk of self-reported bleeding or
out-of-range INR. Third, Shahzad Hasan and colleagues272
in Malaysia conducted a cross-sectional study CAM and
concomitant warfarin usage, finding that of those being
at risk of potential interactions between warfarin–CAM
and warfarin–conventional medicines (such as those
co-consuming fish oil, vitamin E, glucosamine, garlic,
chondroitin and evening primrose oil), there was no
significant difference in the mean INR between CAM and
non-CAM users, and all the patients in the study had INR
values within the target range. Although not
dispositive, collectively the findings from these
studies cited are reassuring as to CAM-warfarin
We must also
remember that (1) most studies and case reports failed
to tightly control for the fact the most patients on
warfarin experience bleeding events and out-of-bounds
INR values, and many also experience clotting events,
independent of CAM usage; (2) many patients on warfarin
may also be on a polpharmacy of traditional medicines
not all of which have been controlled for or even
recognized, and many of which have pharmacokinetics of
not completely known consequence for such adverse events
or potential interactions with warfarin; (3) being on
warfarin, such patients are typically subject to – or
should be under cautious management – regular PT/INR
testing so that out-of-bounds INR readings can be
modulated by adjustment of warfarin dosing. Caution need
still be exercised but given these considerations and
the findings we cited above in this context, it has not
yet been decisively established that CAM supplementation
represents an excessive and clinically relevant
potential for adverse pharmacokinetics with warfarin as
to warrant a contraindication, although it warrants
diligent monitoring of INR readings which, it should be
noted, is however true also for coadministered
traditional medicines and even foods.
Contra CAM But Traditional Medicines Ignored
We draw attention
to the example of cimetidine (Tagamet) for stomach GI
acid complaints: cimetidine is a known and powerful
CYP3A4 inhibitor, and dozens and dozens of chemotherapy
drugs are metabolized by the same enzyme, making for
clinical relevant adverse interactions, yet numerous
studies we have reviewed found that oncologists showed
no professional caution, or even interest in this, among
hundreds of other common adverse interactions among
their patients. So researchers267
at the H. Lee Moffitt Cancer Center and the New Hope
Cancer Center found that 19% - one in five - of cancer
patients were taking cimetidine yet when oncologists
involved were informed about the potentially harmful
clinically relevant drug combinations - which bore FDA
warnings to that effect - not one made any changes in
their patients prescriptions. Similarly, Rachel
Riechelmann and colleagues268
in Sao Paulo concluded in comparable circumstances that
"Curiously, no oncologist made any change in patients’
prescriptions despite being alerted about such
interactions by the authors". This suggests that the
objection to CAM interventions may be more doctrinal
than founded any rational scientific basis, and its
selective application against CAM modalities without any
comparable inquiry into or prohibition against dozens of
traditional medicines far more likely to raise adverse
interactions with cancer therapies reflects unfavorably
on the sincerity of oncologists' prohibitions against
CAM agents; if one is sincerely concerned to minimize
the potential for adverse interactions than that should
apply to traditional and non-traditional interventions
alike, and indifferently, yet regrettably we see no such
equity in display. This ultimately leaves the decision
in the hands of patients, not a burden they should have
to bare alone. Thus, guidance may be stratified and
distinguished by the context:
(1) in the advanced refractory and metastatic disease
context, many potentially beneficial antitumor agents,
both conventional and CAM, may be countenanced given the
well known progress of the disease and the typically
(2) in non-metastatic / non-refractory contexts, the
imperative for such use is muted and caution can be
weighed and balanced; and
(3) in a disease-naive context - as chemopreventive aid
- individual decision can be less constrained as at
least the potential for adverse interaction is not
A search of the
PUBMED, Cochrane Register of Controlled Trials, MEDLINE,
EMBASE, AMED, CINAHL, PsycINFO, (WoS) Web of Science,
BIOSIS, LILACS and Scirus databases was conducted
without language or date restrictions, and updated again
current as of date of publication, with systematic
reviews and meta-analyses extracted separately. Search
was expanded in parallel to include just-in-time (JIT)
medical feed sources as returned from Terkko (provided
by the National Library of Health Sciences - Terkko at
the University of Helsinki). A further "broad-spectrum"
science search using Scirus (410+ million entry
database) was then deployed for resources not otherwise
included. Unpublished studies were located via
contextual search, and relevant dissertations were
located via NTLTD (Networked Digital Library of Theses
and Dissertations) and OpenThesis. Sources in languages
foreign to this reviewer were translated by language
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