title: Disruption of P450-mediated vitamin E hydroxylase activities alters vitamin E status in tocopherol supplemented mice and reveals extra-hepatic vitamin E metabolism.
abstract: The widely conserved preferential accumulation of α-tocopherol (α-TOH) in tissues occurs, in part, from selective postabsorptive catabolism of non-α-TOH forms via the vitamin E-ω-oxidation pathway. We previously showed that global disruption of CYP4F14, the major but not the only mouse TOH-ω-hydroxylase, resulted in hyper-accumulation of γ-TOH in mice fed a soybean oil diet. In the current study, supplementation of Cyp4f14(-/-) mice with high levels of δ- and γ-TOH exacerbated tissue enrichment of these forms of vitamin E. However, at high dietary levels of TOH, mechanisms other than ω-hydroxylation dominate in resisting diet-induced accumulation of non-α-TOH. These include TOH metabolism via ω-1/ω-2 oxidation and fecal elimination of unmetabolized TOH. The ω-1 and ω-2 fecal metabolites of γ- and α-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 ω-, ω-1, and ω-2 TOH hydroxylase activities. TOH-ω-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-ω-hydroxylase activity and other mechanisms in resisting diet-induced accumulation of tissue TOH and further characterize vitamin E metabolism in mice and humans.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
authors.forename: Sabrina A
authors.initials: SA
authors.lastname: Bardowell
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.forename: Robert S
authors.initials: RS
authors.lastname: Parker
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000378:metabolism*; D000072470:Cytochrome P450 Family 4; D019587:Dietary Supplements; D008099:Liver / Q000737:chemistry* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014810:Vitamin E / Q000008:administration & dosage* / Q000378:metabolism*
chemical_list: D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C465342:Cyp4f14 protein, mouse