Flavonoids, potent inhibitors of the human P-form phenolsulfotransferase. Potential role in drug metabolism and chemoprevention

• Published in: Drug metabolism and disposition Vol. 24; no. 2; p. 232
• Main Authors: Eaton, E A, Walle, U K, Lewis, A J, Hudson, T, Wilson, A A, Walle, T
• Format: Journal Article
• Language: English
• Published: United States 01.02.1996
• Subjects: Arylsulfotransferase - antagonists & inhibitors; Biological Availability; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - prevention & control; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacokinetics; Flavonoids - pharmacology; Humans; Isoenzymes - antagonists & inhibitors; Liver Neoplasms - metabolism; Liver Neoplasms - prevention & control; Molecular Structure; Quercetin - pharmacology; Tumor Cells, Cultured
• ISSN: 0090-9556

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.