Activation of cytochrome P450 gene expression in the rat brain by phenobarbital-like inducers

Oxidative biotransformation, coupled with genetic variability in enzyme exp ression, has been the focus of hypotheses interrelating environmental and g enetic factors in the etiology of central nervous system disease processes. Chemical modulation of cerebral cytochrome P450 (P450) monooxygenase expre ssion character may be an important determinant of in situ metabolism, neur oendocrine homeostasis, and/or central nervous system toxicity resulting fr om 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 e valuated the effects of several PR-like inducers on P450 and microsomal epo xide hydrolase gene expression. Animals treated i.p. with four daily doses of PB demonstrated markedly induced levels of CYP2B1, CYP2B2, and CYP3A1 mR NA 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 CYP2 B2 in the brain, although the latter treatments produced marked induction o f the corresponding genes in the liver. Only slight increases in epoxide hy drolase RNA levels resulted in brains of PB-treated animals. Substantial ac tivation of cerebral CYP2B1, CYP2B2, and CYP3A1 mRNA levels also resulted w hen animals were treated with the neuroactive drugs diphenylhydantoin and a mitryptiline, and with the potential PB-like xenobiotic inducers trans-stil bene oxide and diallyl sulfide, whereas dichlorodiphenyltrichloroethane was less efficacious. Although the time course of the induction response is de layed in brain relative to that required for the liver, these results clear ly establish that brain P450s are markedly PB inducible.