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Pregnenolone and dexamethasone, modulators of cytochrome P450‐3A, not increase but reduce urinary α‐CEHC excretion in rats
Author(s) -
Li YiJen,
Shaw HueyMei
Publication year - 2007
Publication title -
biofactors
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.204
H-Index - 94
eISSN - 1872-8081
pISSN - 0951-6433
DOI - 10.1002/biof.5520310107
Subject(s) - endocrinology , medicine , vitamin e , cyp3a , chemistry , alpha tocopherol , excretion , urine , lipid peroxidation , metabolite , metabolism , antioxidant , cytochrome p450 , biology , biochemistry
In this study, the CYP3A inducer pregnenolone‐16α‐carbonitrile (PCN) and the CYP3A inhibitor ketoconazole (KCZ) were used to investigate whether the metabolism of α‐tocopherol to its metabolite, α‐carboxyethyl hydroxychroman (α‐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 α‐tocopherol) or the same diet containing 10‐fold more α‐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 α‐tocopherol levels in the plasma and liver were both significantly decreased by PCN (p < 0.0001), as were α‐CEHC levels in the urine (p = 0.0004). In experiment 2, α‐tocopherol levels in the liver were increased and α‐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 α‐tocopherol levels in the plasma and liver and α‐CEHC levels in the urine. These data showed CYP3A is not a major contributor of the metabolism of α‐tocopherol to α‐CEHC. Nevertheless, vitamin E status was markedly reduced by CYP3A inducers due to increased lipid peroxidation and this would increase the consumption of α‐tocopherol in the liver.