Pregnenolone and dexamethasone, modulators of cytochrome P450-3A, not increase but reduce urinary α-CEHC excretion in rats
Titel:
Pregnenolone and dexamethasone, modulators of cytochrome P450-3A, not increase but reduce urinary α-CEHC excretion in rats
Auteur:
Li, Yi-Jen Shaw, Huey-Mei
Verschenen in:
BioFactors
Paginering:
Jaargang 31 (2008) nr. 2 pagina's 67-76
Jaar:
2008-09-12
Inhoud:
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.
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