Differential effects of neuroleptic agents on hepatic cytochrome P-450 isozymes in the male rat.

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Rane A, Liu Z, Levol R, Bjelfman C, Thyr C, Ericson H, Hansson T, Henderson C, Wolf CR

Differential effects of neuroleptic agents on hepatic cytochrome P-450 isozymes in the male rat.

Biochim Biophys Acta. 1996 Aug 29;1291(1):60-6. doi: 10.1016/0304-4165(96)00046-3.

PubMed ID

8781526 [ View in PubMed

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Abstract

We report the effects of various dopamine receptor-blocking drugs on gene and protein expression, as well as the activity of several hepatic cytochrome P-450 (CYP) enzymes in the male Sprague-Dawley rat. At equipotent doses (with respect to receptor blockade and behavioural tests), the dopamine D2-receptor selective sulpiride and remoxipride gave a conspicuous down-regulation of CYP2C11 and its associated androstenedione 16 alpha-hydroxylation activity as well as of the CYP2C11-specific mRNA. The average immunoidentified CYP2C11 levels correlated with the CYP2C11-specific mRNA levels in all treatment groups (r = 0.994), indicating a transcriptional mechanism. The CYP3A protein was also selectively down-regulated. In contrast, androstenedione 5 alpha-reduction was significantly increased. Clozapine, a non-selective neuroleptic, gave the same effects on the steroid metabolism as sulpiride and remoxipride. In contrast, diverging effects were observed for clozapine, compared to sulpiride and remoxipride, on the immunoidentified CYP1A2, CYP2B1, and CYP3A. These proteins were elevated by clozapine, and down-regulated by sulpiride and remoxipride. Our results are of interest for the interpretation of preclinical dose ranging toxicity tests of neuroleptic agents in rats. They may also be relevant in relation to certain interactions and adverse reactions observed in the clinical use of these drugs. The down-regulation of certain CYP enzymes is most likely mediated by an interaction with the growth hormone secretion.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Remoxipride	Cytochrome P450 1A2	Protein	Humans	Unknown	Inhibitor	Details
Remoxipride	Cytochrome P450 2B1	Protein	Rat	Unknown	Inhibitor	Details
Remoxipride	Cytochrome P450 3A Subfamily (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details