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, chlorpromazine, and thioridazine, or 1 mg/kg of trifluoperazine and perphenazine was administered intraperitoneally for 4 consecutive days. Phenothiazine increased the total CYP content and induced CYP1A, CYP2B, and CYP3A. Western blot analysis showed marked induction of CYP1A1 by phenothiazine. Chlorpromazine induced CYP2B, and CYP3A without a significant increase in the CYP content. Thioridazine decreased the total CYP content and reduced CYP2C11, CYP2E1, and CYP3A. Neither trifluoperazine nor perphenazine significantly altered the catalytic activity or the protein level of any enzyme examined. These results suggest that the antipsychotic phenothiazine derivatives examined here hardly affect CYP1A at the pharmacological doses, while phenothiazine does induce it. Although a relatively short period and small dose of administration might counteract the influence, trifluoperazine and perphenazine have less effect on CYP subfamilies than chlorpromazine or thioridazine.