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.
Highlights
IntroductionThe typical American diet contains 2–4 times as much ␥-TOH as ␣-TOH [1, 2], ␣-TOH is present in the serum and tissues at levels 5–6 times that of ␥-TOH [3]
Supplementary key words -oxidation CYP4F14 cytochrome P450 4F2 (CYP4F2) cytochrome P450 reductase knockout mouse liver intestine fecal elimination diet metabolites
We aimed to investigate whether dietary supplementation with high levels of ␥- and ␦-TOH would overcome the counterbalancing effects and result in tissue enrichment above that seen with the previous soybean oil diet
Summary
The typical American diet contains 2–4 times as much ␥-TOH as ␣-TOH [1, 2], ␣-TOH is present in the serum and tissues at levels 5–6 times that of ␥-TOH [3] This preferential accumulation of ␣-TOH in tissues, termed the ␣-TOH phenotype, is widely conserved in the animal kingdom and occurs despite the fact that all forms of vitamin E exhibit roughly similar radical scavenging activities [4, 5]. We previously identified cytochrome P450 4F2 (CYP4F2) as a human vitamin E-hydroxylase [11], catalyzing the hydroxylation of one of the terminal methyl groups of the hydrophobic side chain This -hydroxylation can be followed by oxidation to the corresponding carboxyl form and a series of side-chain shortening steps, leading to the formation of the 3′ and 5′ carboxychromanol metabolites that can be excreted in the urine [12,13,14].
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call