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Quercetin downregulates matrix metalloproteinases 2 and 9 proteins
expression in prostate cancer cells (PC-3).
Note that quercetin inhibits the xenobiotic
transporter P-gp and the xenobiotic-metabolizing
liver enzyme CYP3A4. Because these two enzymes
represent the major pathways for clearance of
a wide range of cancer chemotherapy drugs,
quercetin may magnify the effects and
side-effects of those drugs. Anyone currently
on cancer chemotherapy who is considering
using quercetin should discuss this with their
physician.
The following review found quercetin to have
dual effects: short-term use downregulated
the activity of the drug clearance enzymes, but
long-term exposure up-regulated transcriptional
expression of the genes for these enzymes
resulting in enhanced activity. Long-term use
of quercetin in advance of discovery of a cancer
may therefore be ill-advised, because it may
enhance resistance to cancer chemotherapy drugs
(and a wide range of other drugs, including
birth control hormones, cardiac medications,
antidepressants, and the anti-organ-rejection
drug cyclosporin).
Life Sci. 2006 Mar 27;78(18):2131-45. Epub 2006 Jan 25.
MDR- and CYP3A4-mediated drug-herbal interactions.
Pal D, Mitra AK.
School of Pharmacy, University of Missouri-Kansas
City, Kansas City, MO 64110-2499, USA.
According to recent epidemiological reports,
almost 40% of American population use
complimentary and alternative medicine (CAM)
during their lifetime. Patients detected with HIV
or cancer often consume herbal products especially
St. John's wort (SJW) for antidepressants in
combination with prescription medicines. Such
self-administered herbal products along with
prescribed medicines raise concerns of therapeutic
activity due to possible drug-herbal interactions.
P-glycoprotein (P-gp) and cytochrome P450 3A4
(CYP3A4) together constitute a highly efficient
barrier for many orally absorbed drugs. Available
literature, clinical reports and in vitro studies
from our laboratory indicate that many drugs and
herbal active constituents are substrates for both
P-gp and CYP3A4. Results from clinical studies and
case reports indicate that self-administered SJW
reduce steady state plasma concentrations of
amitriptyline, cyclosporine, digoxin, fexofenadine,
amprenavir, indonavir, lopinavir, ritonavir,
saquinavir, benzodiazepines, theophyline,
irinotecan, midazolan and warfarin. This herbal
agent has been also reported to cause bleeding
and unwanted pregnancies when concomitantly
administered with oral contraceptives. Most of
these medicinal agents and SJW are substrates
for P-gp and/or CYP3A4. In vitro studies from
our laboratory suggest that short-term exposure
with pure herbal agents such as hypericin,
kaempferol and quercetin or extract of SJW
resulted in higher uptake or influx of ritonavir
and erythromycin. Hypericin, kaempferol and
quercetin also caused a remarkable inhibition
of cortisol metabolism with the percent intact
cortisol values of 64.58%, 89.6% and 90.1%,
respectively, during short-term in vitro
experiments. Conversely, long-term exposure of
herbal agents (hyperforin, kaempferol and
quercetin) showed enhanced expression of CYP3A4
mRNA in Caco-2 cells. In another study, we
observed that long-term exposure of hypericin,
kaempferol, quercetin and silibinin resulted
in higher MDR-1 mRNA expression in Caco-2 cells.
Therefore, herbs can pharmacokinetically act as
inhibitors or inducers. Medicinal agents that
are substrates P-gp-mediated efflux and/or
CYP-mediated metabolism are likely to be
potential candidates for drug-herbal interactions.
The duration of exposure of cells/healthy
volunteers/animals to herbals appears to be
critical for drug-herbal interaction. An increase
in plasma drug concentration is possible during
concomitant administration of SJW and prescribed
drugs. In contrast, prolonged intake of herbal
supplement followed by drug administration may
result in subtherapeutic concentrations. Therefore,
clinical implications of such drug herbal
interactions depend on a variety of factors such as
dose, frequency and timing of herbal intake,
dosing regimen, route of drug administration and
therapeutic range. In vitro screening techniques
will play a major role in identifying possible
herb-drug interactions and thus create a platform
for clinical studies to emerge. Mechanisms of
drug-herbal interaction have been discussed in this
review article.