Biomedical Engineering Reference
In-Depth Information
Two clinical trials have indicated that administration of garlic supplements de-
creased AUC and
C
max
of HIV protease inhibitors saquinavir and ritonavir, substrates
for both CYP3A4 and Pgp.
98
,
99
As suggested by the authors, one mechanism is prob-
ably due to the induction of CYP3A4 in the gut mucosa. However, the contribution
from induction of Pgp cannot be excluded since saquinavir and ritonavir are also Pgp
substrates.
98
,
100
,
101
Green Tea
Green tea is widely consumed as a beverage. Tea polyphenols, known
as catechins, are the major constituents in green tea. The most abundant catechins in
a typical brewed green tea include 10 to 15% (
−
)-epigallocatechin gallate (EGCG),
6 to 10% (
−
)-epigallocatechin (EGC), 2 to 3% (
−
)-epicatechin gallate (ECG), and
)-epicatechin (EC).
102
The extracts of green tea were reported to exhibit a
variety of beneficial health effects, especially chemopreventive, anticarcinogenic,
and antioxidant effects.
103
Several recent studies indicated that green tea components could interact with Pgp
and inhibit its transport activity. In a multidrug-resistant cell line CH
R
C5, green tea
polyphenols (30
2% (
−
g/mL) inhibited the photolabeling of Pgp by 75% and increased the
accumulation of rhodamine 123 threefold. Among the catechins present in green tea,
EGCG, ECG, and (
)-catechin gallate (CG) were the major determinants responsible
for inhibiting Pgp. In addition, EGCG was able to potentiate the cytotoxicity of
vinblastine in CH
R
C5 cells.
104
In carcinoma KB-A1 cells, green tea polyphenols (40
−
g/mL) enhanced doxorubicin cytotoxicity 5.2- and 2.5-fold,
respectively. More detailed studies revealed that green tea polyphenols were able to
inhibit Pgp ATPase activity and down-regulate Pgp expression.
105
The effects of green tea extracts on MRP2 were also investigated. In human
gastrointestinal epithelial LS-180 cells, green tea extracts, at a concentration of
0.01 mg/mL, had no effect on either activity or expression of MRP2. However, at a
concentration of 0.1 mg/mL, green tea extracts significantly inhibited MRP2-mediated
efflux of methotrexate (a MRP2 substrate) in MRP2-overexpressing MDCK (MDCK-
MRP2) cells, resulting in increased cellular accumulation of methotrexate. In contrast
to the inhibitory effects on Pgp, the green tea components EGCG and EGC did not
contribute to the MRP2 inhibition activity.
106
Using Caco-2 and MDCK-MRP cells,
green tea polyphenols such as EGCG, ECG, EGC, and EC were shown to be poten-
tial substrates of MRPs, suggesting the importance of MRPs in determining cellular
concentrations of green tea components.
107
−
109
In a recent study involving 15 herbal extracts, green tea extracts were shown to
potently inhibit OATP-B-mediated uptake of estrone 3-sulfate at the putative gastroin-
testinal concentration (400
g/mL) and EGCG (10
g/mL). Moreover, OATP-B inhibition by green tea ex-
tracts exhibited concentration dependence with an IC
50
value of 22.1
g/mL.
110
In in vivo xenograft studies, green tea extracts were shown to be effective in reversal
of cancer multidrug resistance.
105
,
111
,
112
For example, in mice bearing doxorubicin-
resistant human carcinoma KB-A-1 cells, the combination of doxorubicin with EGCG
(40 mg/kg) increased the doxorubicin concentration in the tumors by 51% and poten-
tiated doxorubicin-induced apoptosis of tumor cells. Compared with the mice given
±
4.9
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