Cytochrome P450-dependent metabolism of vitamin E isoforms is a critical determinant of their tissue concentrations in rats

The aim of this study was to clarify the contribution of cytochrome P450 (CYP)-dependent metabolism of vitamin E isoforms to their tissue concentrations. We studied the effect of ketoconazole, a potent inhibitor of CYP-dependent vitamin E metabolism in cultured cells, on vitamin E concentration in rats. Vitamin E-deficient rats fed a vitamin E-free diet for 4 weeks were administered by oral gavage a vitamin E-free emulsion, an emulsion containing alpha-tocopherol, gamma-tocopherol or a tocotrienol mixture with or without ketoconazole. alpha-Tocopherol was detected in the serum and various tissues of the vitamin E-deficient rats, but gamma-tocopherol, alpha- and gamma-tocotrienol were not detected. Ketoconazole decreased urinary excretion of 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman after alpha-tocopherol or a tocotrienol mixture administration, and that of 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC) after gamma-tocopherol or a tocotrienol mixture administration. The gamma-tocopherol, alpha- and gamma-tocotrienol concentrations in the serum and various tissues at 24 h after their administration were elevated by ketoconazole, while the alpha-tocopherol concentration was not affected. The gamma-tocopherol or gamma-tocotrienol concentration in the jejunum at 3 h after each administration was also elevated by ketoconazole. In addition, significant amount of gamma-CEHC was in the jejunum at 3 h after gamma-tocopherol or gamma-tocotrienol administration, and ketoconazole inhibited gamma-tocopherol metabolism to gamma-CEHC in the jejunum. These results showed that CYP-dependent metabolism of gamma-tocopherol and tocotrienol is a critical determinant of their concentrations in the serum and tissues. The data also suggest that some amount of dietary vitamin E isoform is metabolized by a CYP-mediated pathway in the intestine during absorption.