TY - JOUR
T1 - Cytochrome P4502D4 in the brain
T2 - Specific neuronal regulation by clozapine and toluene
AU - Hedlund, Eva
AU - Wyss, Adrian
AU - Kainu, Tommi
AU - Backlund, Maria
AU - Köhler, Christer
AU - Pelto-Huikko, Markku
AU - Gustafsson, Jan Åke
AU - Warner, Margaret
PY - 1996/8/1
Y1 - 1996/8/1
N2 - Twenty-four hr after a single dose of the neuroleptic drug clozapine, cytochrome P4502D4 (P4502D4) immunoreactivity, which was barely detectable in the brains of untreated rats, was clearly evident in neurons of the substantia nigra pars compacta, ventral tegmental area, granular neurons of the olfactory bulb, and Purkinje and granular neurons of the cerebellum. Induction was maintained with daily administration for 3 weeks. The mRNA for P4502D4 was detected by Northern blotting and localized by in situ hybridization in neurons throughout the brain and in the Bergman glia in the cerebellum. There were no detectable changes in the distribution or quantity of P4502D4 mRNA after treatment with clozapine. The overall P450 content of the brain increased with daily administration to a ~7-fold induction by 3 weeks of clozapine treatment. No induction of 2D4 was observed with the dopamine D2 receptor blockers haloperidol, chlorpromazine, and sulpiride or with the serotonin receptor blocker mianserin. A clozapine-like induction of P4502D4 was obtained on administration of toluene to rats. The specificity of the induction of P4502D4 in the brain with respect to both the drugs that induce it and the cells in which it is induced suggests that induction of this enzyme could be involved in the therapeutic action of clozapine. The similarity of induction of P4502D4 elicited by clozapine and by the neurotoxin toluene suggests that more information is needed before a beneficial or toxicological role can be assigned to this isozyme.
AB - Twenty-four hr after a single dose of the neuroleptic drug clozapine, cytochrome P4502D4 (P4502D4) immunoreactivity, which was barely detectable in the brains of untreated rats, was clearly evident in neurons of the substantia nigra pars compacta, ventral tegmental area, granular neurons of the olfactory bulb, and Purkinje and granular neurons of the cerebellum. Induction was maintained with daily administration for 3 weeks. The mRNA for P4502D4 was detected by Northern blotting and localized by in situ hybridization in neurons throughout the brain and in the Bergman glia in the cerebellum. There were no detectable changes in the distribution or quantity of P4502D4 mRNA after treatment with clozapine. The overall P450 content of the brain increased with daily administration to a ~7-fold induction by 3 weeks of clozapine treatment. No induction of 2D4 was observed with the dopamine D2 receptor blockers haloperidol, chlorpromazine, and sulpiride or with the serotonin receptor blocker mianserin. A clozapine-like induction of P4502D4 was obtained on administration of toluene to rats. The specificity of the induction of P4502D4 in the brain with respect to both the drugs that induce it and the cells in which it is induced suggests that induction of this enzyme could be involved in the therapeutic action of clozapine. The similarity of induction of P4502D4 elicited by clozapine and by the neurotoxin toluene suggests that more information is needed before a beneficial or toxicological role can be assigned to this isozyme.
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M3 - Article
C2 - 8700142
AN - SCOPUS:0029788829
SN - 0026-895X
VL - 50
SP - 342
EP - 350
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 2
ER -