Disruption of P450-mediated vitamin E hydroxylase activities alters vitamin E status in tocopherol supplemented mice and reveals extra-hepatic vitamin E metabolism

The widely conserved preferential accumulation of alpha-tocopherol (alpha-TOH) in tissues occurs, in part, from selective postabsorptive catabolism of non-alpha-TOH forms via the vitamin E-omega-oxidation pathway. We previously showed that global disruption of CYP4F14, the major but not the only mouse TOH-omega-hydroxylase, resulted in hyper-accumulation of gamma-TOH in mice fed a soybean oil diet. In the current study, supplementation of Cyp4f14(-/-) mice with high levels of delta- and gamma-TOH exacerbated tissue enrichment of these forms of vitamin E. However, at high dietary levels of TOH, mechanisms other than omega-hydroxylation dominate in resisting diet-induced accumulation of non-alpha-TOH. These include TOH metabolism via omega-1/omega-2 oxidation and fecal elimination of unmetabolized TOH. The omega-1 and omega-2 fecal metabolites of gamma- and alpha-TOH were observed in human fecal material. Mice lacking all liver microsomal CYP activity due to disruption of cytochrome P450 reductase revealed the presence of extra-hepatic omega-, omega-1, and omega-2 TOH hydroxylase activities. TOH-omega-hydroxylase activity was exhibited by microsomes from mouse and human small intestine; murine activity was entirely due to CYP4F14. These findings shed new light on the role of TOH-omega-hydroxylase activity and other mechanisms in resisting diet-induced accumulation of tissue TOH and further characterize vitamin E metabolism in mice and humans.-Bardowell, S. A., X. Ding, and R. S. Parker. Disruption of P450-mediated vitamin E hydroxylase activities alters vitamin E status in tocopherol supplemented mice and reveals extra-hepatic vitamin E metabolism. J. Lipid Res. 2012. 53: 2667-2676.