TY - JOUR
T1 - Differential effects of neuroleptic agents on hepatic cytochrome P-450 isozymes in the male rat
AU - Rane, Anders
AU - Liu, Zhurong
AU - Levol, Robert
AU - Bjelfman, Catarina
AU - Thyr, Charlotte
AU - Ericson, Hans
AU - Hansson, Tiiu
AU - Henderson, Colin
AU - Wolf, C. Roland
N1 - Funding Information:
We thank Mrs. Birgitta Ask for excellenat ssistancien the laboratorayn dMrs. ElisabethA gell for excellenste cre-tarial help. We also thank Dr. S.-O. Ogren, Astra Arcus AB, for valuablec ommentso n this paper.T his study was supportedb y grants from the Swedish Medical Research Council (04X-04496)a nd the SwedishC ancerSociety.
PY - 1996/8/29
Y1 - 1996/8/29
N2 - We report the effects of various 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 16α-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 5α-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.
AB - We report the effects of various 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 16α-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 5α-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.
KW - Cytochrome P-450
KW - Hepatic regulation
KW - mRNA
KW - Neuroleptic
KW - Rat liver
UR - http://www.scopus.com/inward/record.url?scp=0030605954&partnerID=8YFLogxK
U2 - 10.1016/0304-4165(96)00046-3
DO - 10.1016/0304-4165(96)00046-3
M3 - Article
C2 - 8781526
AN - SCOPUS:0030605954
SN - 0304-4165
VL - 1291
SP - 60
EP - 66
JO - BBA - General Subjects
JF - BBA - General Subjects
IS - 1
ER -