title: Pregnenolone and dexamethasone, modulators of cytochrome P450-3A, not increase but reduce urinary alpha-CEHC excretion in rats.
abstract: In this study, the CYP3A inducer pregnenolone-16alpha-carbonitrile (PCN) and the CYP3A inhibitor ketoconazole (KCZ) were used to investigate whether the metabolism of alpha-tocopherol to its metabolite, alpha-carboxyethyl hydroxychroman (alpha-CEHC), is CYP3A-dependent in rats. In experiment 1, two groups of Wistar rats were fed for 3 wk with either a basal diet (containing 50 ppm of alpha-tocopherol) or the same diet containing 10-fold more alpha-tocopherol. In the last 3 days, each group was divided into 2 subgroups which were given a single i.p. injection of either PCN at 75 mg/kg/d (P50 & P500 groups) or DMSO (D50 & D500 groups). The liver TBARS concentration was highest in the P50 group. Two-way ANOVA analysis showed that alpha-tocopherol levels in the plasma and liver were both significantly decreased by PCN (p < 0.0001), as were alpha-CEHC levels in the urine (p = 0.0004). In experiment 2, alpha-tocopherol levels in the liver were increased and alpha-CEHC excretion in the urine decreased in the Wistar rats fed with KCZ containing diet. In experiment 3, Wistar rats administered with dexamethasone (DEX) significantly decreased alpha-tocopherol levels in the plasma and liver and alpha-CEHC levels in the urine. These data showed CYP3A is not a major contributor of the metabolism of alpha-tocopherol to alpha-CEHC. Nevertheless, vitamin E status was markedly reduced by CYP3A inducers due to increased lipid peroxidation and this would increase the consumption of alpha-tocopherol in the liver.
authors.affiliation: Laboratory of Nutritional Biochemistry, Institute of Microbiology and Biochemistry, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Li
authors.forename: Huey-Mei
authors.initials: HM
authors.lastname: Shaw
mesh_terms: D000818:Animals; D002839:Chromans / Q000652:urine*; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D011422:Propionates / Q000652:urine*; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D024502:alpha-Tocopherol / Q000378:metabolism
chemical_list: D002839:Chromans; D011422:Propionates; D017392:Thiobarbituric Acid Reactive Substances; D011285:Pregnenolone Carbonitrile; C084852:2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A; D024502:alpha-Tocopherol; D007654:Ketoconazole