| ABSTRACT: |
|
The common dietary constituent quercetin was a potent inhibitor of
sulfoconjugation of acetaminophen and minoxidil by human liver cytosol,
partially purified P-form phenolsulfotransferase (PST), and recombinant
P-form PST, with IC50 values of 0.025-0.095 microM. Quercetin inhibition
of acetaminophen was noncompetitive with respect to acceptor substrate,
with a Ki value of 0.067 microM. A number of other flavonoids, such as
fisetin, galangin, myricetin, kaempferol, chrysin, and apigenin, were also
potent inhibitors of P-form PST-mediated sulfation, with IC50 values <
1 microM. Studies of structural analogs indicated the flavonoid 7-hydroxyl
group as particularly important for potent inhibition. Potential human
metabolites of quercetin were poor inhibitors. Curcumin, genistein, and
ellagic acid (other polyphenolic natural products) were also inhibitors of
P-form PST, with IC50 values of 0.38-34.8 microM. Quercetin was also shown
to inhibit sulfoconjugation by the human hepatoma cell line Hep G2.
Although less potent in this intact cell system (IC50 2-5 microM),
quercetin was still more potent than 2,6-dichloro-4-nitrophenol, the
classical P-form PST inhibitor that has been shown to be an inhibitor also
in vivo. These observations suggest the potential for clinically important
drug interactions, as well as a possible role for flavonoids as
chemopreventive agents in sulfation-induced carcinogenesis. |