RT Journal Article SR Electronic T1 STRONG INHIBITORY EFFECTS OF COMMON TEA CATECHINS AND BIOFLAVONOIDS ON THE O-METHYLATION OF CATECHOL ESTROGENS CATALYZED BY HUMAN LIVER CYTOSOLIC CATECHOL-O-METHYLTRANSFERASE JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 497 OP 504 DO 10.1124/dmd.32.5.497 VO 32 IS 5 A1 Mime Nagai A1 Allan H. Conney A1 Bao Ting Zhu YR 2004 UL http://dmd.aspetjournals.org/content/32/5/497.abstract AB In the present investigation, we studied the inhibitory effects of three tea catechins [catechin, epicatechin, and (-)-epigallocatechin-3-O-gallate] and two bioflavonoids (quercetin and fisetin) on the O-methylation of 2- and 4-hydroxyestradiol (2-OH-E2 and 4-OH-E2, respectively) by human liver cytosolic catechol-O-methyltransferase (COMT). We found that catechin and epicatechin each inhibited the O-methylation of 2-OH-E2 and 4-OH-E2 in a concentration-dependent manner. The IC50 values for inhibition of 2-OH-E2 methylation by catechin and epicatechin were 14 to 17 μM and 44 to 65 μM, respectively, and their IC50 values for inhibition of 4-OH-E2 methylation were 5 to 7 μM and 10 to 18 μM, respectively. Our data showed that these two catechins had 2- to 6-fold higher inhibition potency for the O-methylation of 4-OH-E2 than for the O-methylation of 2-OH-E2. (-)-Epigallocatechin-3-O-gallate was found to have a distinctly high inhibition potency for the O-methylation of 2- and 4-OH-E2 (IC50 values of 0.04–0.07 μM and 0.2–0.5 μM, respectively). The crude extracts from green tea and black tea also showed very strong activity in inhibiting human liver COMT-mediated O-methylation of catechol estrogens. We also determined, for comparison, two common bioflavonoids (quercetin and fisetin) for their inhibitory effects on human liver COMT-mediated O-methylation of catechol estrogens. The IC50 values for quercetin and fisetin were 0.9 to 1.5 μM and 3.3 to 4.5 μM, respectively, for inhibiting the O-methylation of 2-OH-E2, and 0.5 to 1.2 μM and 2.6 to 4.2 μM, respectively, for inhibiting the O-methylation of 4-OH-E2. Enzyme kinetic analyses showed that both tea catechins and bioflavonoids inhibited human liver COMT-mediated O-methylation of 4-OH-E2 (a representative substrate) with a mixed mechanism of inhibition (competitive plus noncompetitive). In summary, the catechol-containing tea catechins and bioflavonoids are strong inhibitors of human liver COMT-mediated O-methylation of catechol estrogens. More studies are warranted to determine the extent of such inhibition in human subjects and the potential biological consequences. The American Society for Pharmacology and Experimental Therapeutics