Cytochrome P4503A-dependent metabolism of tocopherols and inhibition by sesamin.
Carboxychroman metabolites of the major dietary tocopherols are excreted in human urine, but the mechanism of their synthesis is unknown. We employed well-characterized inhibitors of specific cytochrome P-450 (CYP) enzymes to determine which form was likely involved in tocopherol side chain oxidation. Ketoconozole (1.0 microM), a potent and selective inhibitor of CYP3A, substantially inhibited metabolism of gamma- and alpha-tocopherol in rat primary hepatocytes, and metabolism of gamma- and delta-tocopherol in HepG2/C3A cells. Sulphaphenazole and cyclosporin, inhibitors of CYP2C and CYP27, respectively, were without effect. Sesamin, a sesame lignan that causes elevation of tissue tocopherol concentration in rats, strongly inhibited tocopherol metabolism by HepG2/C3A cells at 1.0 microM. These results support a CYP3A-dependent mechanism of side chain metabolism of tocopherols to water-soluble carboxychromans, and provide the first evidence of a specific enzyme involved in vitamin E metabolism. The data further suggest that sesamin increases tissue tocopherol concentration by inhibiting tocopherol catabolism.
Parker
R S
RS
Division of Nutritional Sciences, Cornell University, Ithaca, New York, 14853, USA. rsp3@cornell.edu
Sontag
T J
TJ
Swanson
J E
JE
D000975:Antioxidants / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology; D017705:Lignans / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000378:metabolism*
D000975:Antioxidants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004149:Dioxoles; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D017705:Lignans; D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D007654:Ketoconazole; C054125:sesamin