Metabolism of caffeic acid by isolated rat hepatocytes and subcellular fractions.
Caffeic acid (CA) is found in a wide variety of foods such as vegetables, fruits, tea, coffee, and wine. However, enzymes involved in its metabolism have not been identified. In the following, caffeic (CA), chlorogenic (CGA), and dihydrocaffeic (DHCA) acids were incubated with hepatocytes and shown to undergo metabolism by cytochrome P450, catechol-O-methyltransferase (COMT), and beta-oxidation enzymes. Ferulic (FA) or dihydroferulic (DHFA) acids, formed as the result of CA- or DHCA-O-methylation by COMT, were also O-demethylated by CYP1A1/2 but not CYP2E1. DHCA or DHFA also underwent side chain dehydrogenation to form CA and FA, respectively, which was prevented by thioglycolic acid, an inhibitor of the beta-oxidation enzyme acyl CoA dehydrogenase. The rates of glutathione conjugate formation catalyzed by NADPH/microsomes (CYP2E1) in decreasing order DHCA>CA>CGA trend which was in reverse order to the rates of their O-methylation by COMT. The CA- and DHCA-o-quinones formed by NADPH/P450 likely inhibited COMT but can readily form glutathione conjugates. CA, DHCA and DHFA were inter-metabolized to each other and to FA by isolated rat hepatocytes whereas FA was metabolized only to CA but not to DHCA or DHFA. CA, DHCA, FA, DHFA and CGA showed a dose-dependent hepatocyte toxicity and the LD(50) (2 h), determined were in decreasing order of effectiveness DHCA>CA>DHFA>CGA>FA. In summary, evidence has been provided that O-methylation, GSH conjugation, hydrogenation and dehydrogenation are involved in the hepatic metabolism of CA and DHCA. The O-methylation pathway for CA and DHCA is a detoxification route whereas o-quinones formation catalyzed by P450 is the toxification route.
Moridani
Majid Y
MY
Department of Laboratory Medicine and Pathobiology, Mount Sinai Hospital, University of Toronto, 600 University Avenue, Ont., Canada M5G 1X5.
Scobie
Hugh
H
O'Brien
Peter J
PJ
D000818:Animals; D002109:Caffeic Acids / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D002396:Catechols / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003640:Dealkylation; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006865:Hydrogenation; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008745:Methylation; D008862:Microsomes, Liver / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010636:Phenols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000378:metabolism*
D002109:Caffeic Acids; D002396:Catechols; D010636:Phenols; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D002394:Catechol O-Methyltransferase; D005978:Glutathione; C040048:caffeic acid