DIFFERENTIAL-EFFECTS OF NEUROLEPTIC AGENTS ON HEPATIC CYTOCHROME-P-450 ISOZYMES IN THE MALE-RAT

We report the effects of various dopamine receptor-blocking drugs on g ene and protein expression, as well as the activity of several hepatic cytochrome P-450 (CYP) enzymes in the male Sprague-Dawley rat. At equ ipotent doses (with respect to receptor blockade and behavioural tests ), the dopamine D-2-receptor selective sulpiride and remoxipride gave a conspicuous down-regulation of CYP2C11 and its associated androstene dione 16 alpha-hydroxylation activity as well as of the CYP2C11-specif ic mRNA. The average immunoidentified CYP2C11 levels correlated with t he CYP2C11-specific mRNA levels in all treatment groups (r = 0.094), i ndicating a transcriptional mechanism. The CYP3A protein was also sele ctively down-regulated. In contrast. androstenedione 5 alpha-reduction was significantly increased. Clozapine, a non-selective neuroleptict gave the same effects on the steroid metabolism as sulpiride and remox ipride. In contrast, diverging effects were observed for clozapine, co mpared to sulpiride and remoxipride, on the immunoidentified CYP1A2, C YP2B1. and CYP3A. These proteins were elevated by clozapine, and down- regulated by sulpiride and remoxipride. Our results are of interest fo r the interpretation of preclinical dose ranging toxicity tests of neu roleptic agents in rats. They may also be relevant in relation to cert ain interactions and adverse reactions observed in the clinical use of these drugs. The down-regulation of certain CYP enzymes is most likel y mediated by an interaction with the growth hormone secretion.