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 oxidatio n. Ketoconozole (1.0 muM), a potent and selective inhibitor of CYP3A, subst antially inhibited metabolism of gamma- and cu-tocopherol in rat primary he patocytes, and metabolism of gamma- and delta -tocopherol in HepG2/C3A cell s. Sulphaphenazole and cyclosporin, inhibitors of CYP2C and CYP27, respecti vely, were without effect. Sesamin, a sesame lignan that causes elevation o f tissue tocopherol concentration in rats, strongly inhibited tocopherol me tabolism by HepG2/C3A cells at 1.0 muM These results support a CYP3A-depend ent mechanism of side chain metabolism of tocopherols to water-soluble carb oxychromans, and provide the first evidence of a specific enzyme involved i n vitamin E metabolism. The data further suggest that sesamin increases tis sue tocopherol concentration by inhibiting tocopherol catabolism. (C) 2000 Academic Press.