Activation of cytochrome P450 gene expression in the rat brain by phenobarbital-like inducers.
Oxidative biotransformation, coupled with genetic variability in enzyme expression, has been the focus of hypotheses interrelating environmental and genetic factors in the etiology of central nervous system disease processes. Chemical modulation of cerebral cytochrome P450 (P450) monooxygenase expression character may be an important determinant of in situ metabolism, neuroendocrine homeostasis, and/or central nervous system toxicity resulting from exposure to neuroactive drugs and xenobiotic substances. To examine the capacity of the rat brain to undergo phenobarbital (PB)-mediated induction, we developed reverse transcription-polymerase chain reaction methods and evaluated the effects of several PB-like inducers on P450 and microsomal epoxide hydrolase gene expression. Animals treated i.p. with four daily doses of PB demonstrated markedly induced levels of CYP2B1, CYP2B2, and CYP3A1 mRNA in the striatum and cerebellum. In contrast, 1 or 2 days of PB treatment resulted in unchanged or even slightly decreased levels of CYP2B1 and CYP2B2 in the brain, although the latter treatments produced marked induction of the corresponding genes in the liver. Only slight increases in epoxide hydrolase RNA levels resulted in brains of PB-treated animals. Substantial activation of cerebral CYP2B1, CYP2B2, and CYP3A1 mRNA levels also resulted when animals were treated with the neuroactive drugs diphenylhydantoin and amitryptiline, and with the potential PB-like xenobiotic inducers trans-stilbene oxide and diallyl sulfide, whereas dichlorodiphenyltrichloroethane was less efficacious. Although the time course of the induction response is delayed in brain relative to that required for the liver, these results clearly establish that brain P450s are markedly PB inducible.
Schilter
B
B
Department of Environmental Health, University of Washington, Seattle 98195-6099, USA.
Andersen
M R
MR
Acharya
C
C
Omiecinski
C J
CJ
D000498:Allyl Compounds / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D001921:Brain / Q000201:enzymology*; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000235:genetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D003634:DDT / Q000494:pharmacology; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics; D010634:Phenobarbital / Q000494:pharmacology*; D010672:Phenytoin / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology
D000498:Allyl Compounds; D012333:RNA, Messenger; D013267:Stilbenes; D013440:Sulfides; D000639:Amitriptyline; C038491:allyl sulfide; D010672:Phenytoin; D003577:Cytochrome P-450 Enzyme System; D003634:DDT; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C465138:Cyp3a23-3a1 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; C025619:steroid 16-beta-hydroxylase; D004851:Epoxide Hydrolases; C025906:stilbene oxide; D010634:Phenobarbital