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Discovery, Characterization, and Significance of the Cytochrome P450 ω‐Hydroxylase Pathway of Vitamin E Catabolism

Abstract: Tocopherols are known to undergo metabolism to phytyl chain‐shortened metabolites excreted in urine. We sought to characterize the pathway, including associated enzymes, involved in this biotransformation. We previously found that human hepatoblastoma (HepG2) cultures metabolized tocopherols to their corresponding short‐chain carboxychromanols. Putative metabolites of γ‐tocopherol that contained intact chromanol moieties were structurally identified using HepG2 cultures and electron impact gas chromatography‐mass spectrometry. A microsomal assay for synthesis of the initial ω‐oxidation metabolites was developed and used to screen several recombinant human liver cytochrome P450 isozymes for ω‐hydroxylase activity. Seven metabolites of γ‐tocopherol were identified in HepG2 cultures, including 13′‐hydroxy‐γ‐TOH and all six carboxychromanols predicted by sequential ω‐oxidation truncation. Rat and human liver microsomes catalyzed synthesis of 13′‐OH‐ and 13′‐COOH‐γ‐TOH, but not other metabolites, in the presence of NADPH. Inclusion of NAD favored synthesis of the 13′‐COOH metabolite. Recombinant CYP4F2, but not other major human liver CYP isoforms (including CYP3A4 and 3A7), exhibited tocopherol‐ω‐hydroxylase activity. Liver microsomes and recombinant CYP4F2 both exhibited substrate preference for γ‐TOH over α‐TOH, and recent studies show that tocotrienols are catabolized more extensively than the corresponding tocopherols. Comparative rates of ω‐oxidation of tocochromanols in hepatocytes are inversely related to biopotency and directly related to cytotoxicity of these substances in macrophages. The liver contains a cytochrome P450‐mediated pathway that preferentially catabolizes “non‐α” tocochromanols to excretable metabolites. This metabolic pathway appears central to the optimization of tissue tocochromanol status.