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 α-tocopherol, γ-tocopherol or a tocotrienol mixture with or without ketoconazole. α-Tocopherol was detected in the serum and various tissues of the vitamin E-deficient rats, but γ-tocopherol, α- and γ-tocotrienol were not detected. Ketoconazole decreased urinary excretion of 2,5,7,8-tetramethyl-2(2′-carboxyethyl)-6-hydroxychroman after α-tocopherol or a tocotrienol mixture administration, and that of 2,7,8-trimethyl-2(2′-carboxyethyl)-6-hydroxychroman (γ-CEHC) after γ-tocopherol or a tocotrienol mixture administration. The γ-tocopherol, α- and γ-tocotrienol concentrations in the serum and various tissues at 24 h after their administration were elevated by ketoconazole, while the α-tocopherol concentration was not affected. The γ-tocopherol or γ-tocotrienol concentration in the jejunum at 3 h after each administration was also elevated by ketoconazole. In addition, significant amount of γ-CEHC was in the jejunum at 3 h after γ-tocopherol or γ-tocotrienol administration, and ketoconazole inhibited γ-tocopherol metabolism to γ-CEHC in the jejunum. These results showed that CYP-dependent metabolism of γ-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.