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 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.
Rane
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A
Department of Clinical Pharmacology, University Hospital, Uppsala University, Sweden. Anders.Rane@klinfarm.uu.se
Liu
Z
Z
Levol
R
R
Bjelfman
C
C
Thyr
C
C
Ericson
H
H
Hansson
T
T
Henderson
C
C
Wolf
C R
CR
D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D003687:Dehydroepiandrosterone / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D015536:Down-Regulation; D005036:Ethylmorphine / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase
D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D007527:Isoenzymes; D012333:RNA, Messenger; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D005036:Ethylmorphine