α-Tocopherol modulates Cyp3a expression, increases γ-CEHC production, and limits tissue γ-tocopherol accumulation in mice fed high γ-tocopherol diets

Although all forms of vitamin E are absorbed, the liver preferentially secretes α-, but not γ-tocopherol, into plasma. Liver α-tocopherol secretion is under the control of the α-tocopherol transfer protein (TTP). Therefore, to assess γ-tocopherol bioactivities Ttpa−/−, +/− and +/+ mice were fed for 5 weeks diets containing γ-tocopherol 550 (γ-T550), γ-tocopherol 60 (γ-T60) mg/kg that also contained trace amounts of α-tocopherol, a vitamin E-deficient diet, or a control diet. Plasma and tissues from mice fed γ-T550 diets were found to contain similar γ- and α-tocopherol concentrations despite the high dietary γ-tocopherol content; nervous tissues contained almost no γ-tocopherol. Liver vitamin E metabolites (carboxyethyl hydroxychromans, CEHCs) were also measured. In mice with widely ranging liver α- (from 0.7 to 16 nmol/g) and γ-tocopherol concentrations (0 to 13 nmol/g), hepatic α-CEHC was undetectable, but γ-CEHC concentrations (0.1 to 0.8 nmol/g) were correlated with both α- and γ-tocopherol concentrations (P < 0.004). Hepatic cytochrome P450s (CYPs) involved in vitamin E metabolism, Cyp4f and Cyp3a, were also measured. There were no variations in Cyp4f protein expression as related to diet or mouse genotype. However, Cyp3a was correlated (P < 0.0001) with liver α-, but not γ-tocopherol concentrations. These data support the hypothesis that α-tocopherol modulates xenobiotic metabolism by increasing Cyp3a expression, γ-CEHC formation, and the excretion of both γ-tocopherol and γ-CEHC.