Abstract
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.
Footnotes
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↵1 Abbreviations used are: 2-OH-E2, 2-hydroxyestradiol; 4-OH-E2, 4-hydroxyestradiol; COMT, catechol-O-methyltransferase; SAM, S-adenosyl-l-methionine; EGCG, (-)-epigallocatechin-3-O-gallate; BTP, black tea polyphenol(s); GTP, green tea polyphenol(s); SAH, S-adenosyl-l-homocysteine.
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Supported in part by grants from the National Institutes of Health (RO1 CA 97109), the American Parkinson Disease Association, and the California Table Grape Commission.
- Received November 24, 2003.
- Accepted January 29, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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