A comparison of the effect of five phenothiazines on hepatic CYP isoenzymes in rats

We examined the influence of five phenothiazine derivatives on the activity and the expression of hepatic cytochrome P450 (CYP) 1A, 2B, 2C6, 2C11, 2E1 and 3A2 in male Sprague-Dawley rats. Twenty mg/kg of phenothiazine, chlorp romazine. and thioridazine, or 1 mg/kg of trifluoperazine and perphenazine was administered intraperitoneally for 4 consecutive days. Phenothiazine in creased the total CYP content and induced CYP1A, CYP2B, and CYP3A. Western blot analysis showed marked induction of CYP1A1 by phenothiazine. Chlorprom azine induced CYP2B, and CYP3A without a significant increase in the CYP co ntent. Thioridazine decreased the total CYP content and reduced CYP2C11, CY P2E1, and CYP3A. Neither trifluoperazine nor perphenazine significantly alt ered the catalytic activity or the protein level of any enzyme examined. Th ese results suggest that the antipsychotic phenothiazine derivatives examin ed here hardly affect CYP1A at the pharmacological doses, while phenothiazi ne does induce it. Although a relatively short period and smalt dose of adm inistration might counteract the influence, trifluoperazine and perphenazin e have less effect on CYP subfamilies than chlorpromazine or thioridazine.