title: Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation.
abstract: The metabolism of tocopherols by omega- and beta-oxidation of the phytyl side chain has been inferred from the identification of the final products carboxyethyl-hydroxychromans (CEHC) and immediate precursors, alpha- and gamma-carboxymethylbutyl-hydroxychromans (CMBHCs). This hypothesis is here corroborated by the identification of a further alpha-tocopherol metabolite, alpha-carboxymethylhexyl-hydroxychroman (alpha-CMHHC), and evidence for the involvement of a P450-type cytochrome. HepG2 cells, when exposed to 100 microM all-rac-alpha-tocopherol, released alpha-CEHC, alpha-CMBHC, and alpha-CMHHC into the medium. The detection of those metabolites required pretreatment of the cells with alpha-tocopherol for 10 d. In contrast, analogous metabolites of gamma and delta-tocopherol were detectable without any preconditioning, while corresponding metabolites of RRR-alpha-tocopherol could not be detected at all. The formation of alpha-CEHC from all-rac-alpha-tocopherol was enhanced up to 5-fold by pretreatment of the HepG2 cells with rifampicin, known to induce CYP3A-type cytochromes with the capability of catalyzing omega-oxidation. In contrast, clofibrate did not reveal any effect. This observation suggests that a CYP3A-type cytochrome initiates tocopherol metabolism by omega-oxidation. It further reveals that inducible omega-oxidation is the rate-limiting step in tocopherol metabolism. It is discussed that competition of microsomal omega-oxidation with specific binding by the alpha-tocopherol transfer protein (alpha-TTP) determines the metabolic fate of the individual tocopherols.
authors: Department of Vitamins and Atherosclerosis, German Institute of Human Nutrition, Bergholz-Rehbruecke, Germany.
authors: M
authors: M
authors: Birringer
authors: D
authors: D
authors: Drogan
authors: R
authors: R
authors: Brigelius-Flohe
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases; D001693:Biological Transport, Active; D002460:Cell Line; D002839:Chromans / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D010084:Oxidation-Reduction; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010421:Pentanoic Acids / Q000378:metabolism; D011422:Propionates / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D024505:Tocopherols / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C434334:5-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl)-2-methyl-pentanoic acid; D002839:Chromans; D005609:Free Radicals; D010421:Pentanoic Acids; D011422:Propionates; C084852:2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D024505:Tocopherols; D012293:Rifampin