STRONG INHIBITORY EFFECTS OF COMMON TEA CATECHINS AND BIOFLAVONOIDS ON THE O-METHYLATION OF CATECHOL ESTROGENS CATALYZED BY HUMAN LIVER CYTOSOLIC CATECHOL-O-METHYLTRANSFERASE

• Published in: Drug metabolism and disposition Vol. 32; no. 5; pp. 497 - 504
• Main Authors: NAGAI, Mime, CONNEY, Allan H, BAO TING ZHU
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.05.2004
• Subjects: Antineoplastic agents; Biological and medical sciences; Catalysis; Catechin - isolation & purification; Catechin - pharmacology; Catechol O-Methyltransferase - metabolism; Catechol O-Methyltransferase Inhibitors; Cytosol - drug effects; Cytosol - enzymology; Dose-Response Relationship, Drug; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - pharmacology; Estrogens, Catechol - metabolism; Flavonoids - isolation & purification; Flavonoids - pharmacology; General aspects; Humans; Liver - drug effects; Liver - enzymology; Medical sciences; Methylation - drug effects; Pharmacology. Drug treatments; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Tea; Human; Catechin; Digestive system; Enzyme; Transferases; Liver; Estrogen; Catechol O-methyltransferase; Pyrocatechol; Metabolism; Cytosol; Flavonoid; Ovarian hormone; Tea; Polyphenol; Methyltransferases; Plant origin; Phenols; Drug interaction; Sex steroid hormone; Methylation
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.32.5.497

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-E 2 and 4-OH-E 2 , respectively) by human liver cytosolic catechol- O -methyltransferase (COMT). We found that catechin and epicatechin each inhibited the O -methylation of 2-OH-E 2 and 4-OH-E 2 in a concentration-dependent manner. The IC 50 values for inhibition of 2-OH-E 2 methylation by catechin and epicatechin were 14 to 17 μM and 44 to 65 μM, respectively, and their IC 50 values for inhibition of 4-OH-E 2 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-E 2 than for the O -methylation of 2-OH-E 2 . (-)-Epigallocatechin-3- O -gallate was found to have a distinctly high inhibition potency for the O -methylation of 2- and 4-OH-E 2 (IC 50 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 IC 50 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-E 2 , and 0.5 to 1.2 μM and 2.6 to 4.2 μM, respectively, for inhibiting the O -methylation of 4-OH-E 2 . Enzyme kinetic analyses showed that both tea catechins and bioflavonoids inhibited human liver COMT-mediated O -methylation of 4-OH-E 2 (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.