Inhibition of human catechol-O-methyltransferase (COMT)-mediated O-methylation of catechol estrogens by major polyphenolic components present in coffee.
In the present study, we investigated the inhibitory effect of three catechol-containing coffee polyphenols, chlorogenic acid, caffeic acid and caffeic acid phenethyl ester (CAPE), on the O-methylation of 2- and 4-hydroxyestradiol (2-OH-E(2) and 4-OH-E(2), respectively) catalyzed by the cytosolic catechol-O-methyltransferase (COMT) isolated from human liver and placenta. When human liver COMT was used as the enzyme, chlorogenic acid and caffeic acid each inhibited the O-methylation of 2-OH-E(2) in a concentration-dependent manner, with IC(50) values of 1.3-1.4 and 6.3-12.5 microM, respectively, and they also inhibited the O-methylation of 4-OH-E(2), with IC(50) values of 0.7-0.8 and 1.3-3.1 microM, respectively. Similar inhibition pattern was seen with human placental COMT preparation. CAPE had a comparable effect as caffeic acid for inhibiting the O-methylation of 2-OH-E(2), but it exerted a weaker inhibition of the O-methylation of 4-OH-E(2). Enzyme kinetic analyses showed that chlorogenic acid and caffeic acid inhibited the human liver and placental COMT-mediated O-methylation of catechol estrogens with a mixed mechanism of inhibition (competitive plus noncompetitive). Computational molecular modeling analysis showed that chlorogenic acid and caffeic acid can bind to human soluble COMT at the active site in a similar manner as the catechol estrogen substrates. Moreover, the binding energy values of these two coffee polyphenols are lower than that of catechol estrogens, which means that coffee polyphenols have higher binding affinity for the enzyme than the natural substrates. This computational finding agreed perfectly with our biochemical data.
Zhu
Bao Ting
BT
Department of Pharmacology, Toxicology and Therapeutics, School of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. BTZhu@kumc.edu
Wang
Pan
P
Nagai
Mime
M
Wen
Yujing
Y
Bai
Hyoung-Woo
HW
D000328:Adult; D055162:Biocatalysis / Q000187:drug effects; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000737:chemistry; D065098:Catechol O-Methyltransferase Inhibitors; D002726:Chlorogenic Acid / Q000737:chemistry / Q000494:pharmacology; D003069:Coffee / Q000737:chemistry*; D019295:Computational Biology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D002393:Estrogens, Catechol / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D008745:Methylation / Q000187:drug effects; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D059808:Polyphenols; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary
D002109:Caffeic Acids; D065098:Catechol O-Methyltransferase Inhibitors; D003069:Coffee; D002393:Estrogens, Catechol; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D002726:Chlorogenic Acid; D002394:Catechol O-Methyltransferase; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol