Biomedical Engineering Reference
In-Depth Information
with chrysin (IC
50
=
4
.
6
±
0
.
5
M), the inhibitory potency of 6-prenylchrysin was
enhanced significantly (IC
50
=
M). Moreover, 6-prenylchrysin seemed
to represent a specific BCRP inhibitor since no interaction was detected with either
Pgp or MRP1.
166
0
.
29
±
0
.
06
Interactions withOATP
In a recent study, 20 naturally occurring flavonoids and some
of their corresponding glycosides were investigated for their modulatory effects on
OATP-C by using [
3
H]dehydroepiandrosterone sulfate (DHEAS) as a probe substrate.
Many of the flavonoids tested (including biochanin A, genistein, and epigallocatechin-
3-gallate) inhibited [
3
H]DHEAS uptake significantly in a concentration-dependent
manner, with biochanin A being one of the most potent inhibitors, with an IC
50
of 11.3
±
M. A kinetic study revealed that biochanin A inhibited [
3
H]DHEAS uptake
in a noncompetitive manner with a
K
i
value of 10.2
3.22
M. Four of the eight pairs
of tested flavonoids and their glycosides [i.e., genistein/genistin, diosmetin/diosmin,
epigallocatechin (EGC)/epigallocatechin-3-gallate (EGCG), and quercetin/rutin] ex-
hibited distinct effects on [
3
H]DHEAS uptake. For example, genistin did not inhibit
DHEAS uptake whereas genistein did, and rutin stimulated uptake whereas quercetin
had no effect
36
(Table 22.6). In another study using HEK293 cells stably transfected
with OATP-B, Fuchikami et al. identified that some flavanols from green tea extracts
(e.g., catechin, EC, EGC, ECG, EGCG) were potent inhibitors of OATP-B. At a
concentration as low as 10
±
1.89
M, EC, ECG, and EGCG significantly inhibited OATP-
B-mediated uptake of estrone-3 sulfate.
110
Similar to Pgp inhibition, the presence of
a galloyl moiety on the C ring of green tea catechins (e.g., EGCG vs. EGC, ECG vs.
EC) markedly enhanced their potency in both OATP-B and OATP-C inhibition.
36
,
110
22.2.3. Interactions of Organic Isothiocyanates with Drug Transporters
Organic isothiocyanates (ITCs, R N C S), also known as mustard oils, are
widely present in cruciferous vegetables, such as broccoli, watercress, cabbage, and
cauliflower. Human consumption of glucosinolates, the precursors of ITCs in plants,
has been estimated as high as 300 mg/day, and milligram quantities of ITCs can
be released from consumption of normal amounts of vegetables.
167
,
168
Recently, di-
etary supplements containing ITCs have been used increasingly, due to the beneficial
health effects of ITCs, especially cancer chemopreventive effects.
169
,
170
However, the
mechanisms of ITCs in cancer chemoprevention have not been fully characterized.
Recently, a number of studies have indicated that ITCs might reverse resistance
to anticancer drugs via interacting with drug transporters. Using Pgp-overexpressing
MCF-7/ADR and MRP1-overexpressing Panc-1 cells, Tseng et al.
171
evaluated the
effects of ITCs on Pgp- and MRP1-mediated transport of chemotherapeutic agents.
Among all the ITCs tested, 1-naphthyl-isothiocyanate (NITC) increased the accu-
mulation of daunomycin (DNM) and vinblastine (VBL) significantly in both resis-
tant cell lines. Benzylisothiocyanate (BITC) and phenylhexylisothiocyanate (PHITC)
increased the accumulation of DNM and/or VBL in MCF-7/ADR cells signifi-
cantly, whereas phenethylisothiocyanate (PEITC), erysolin, PHITC, and phenylbutyl-
isothiocyanate (PBITC) increased the accumulation of DNM and/or VBL in Panc-1
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