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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Activation of Cytochrome P450 Gene Expression in the Rat Brain by Phenobarbital-Like Inducers

Benoît Schilter, Mark R. Andersen, Chetana Acharya and Curtis J. Omiecinski
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 916-922;
Benoît Schilter
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Mark R. Andersen
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Chetana Acharya
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Curtis J. Omiecinski
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Abstract

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.

Footnotes

  • Send reprint requests to: Curtis J. Omiecinski, Ph.D., Department of Environmental Health, University of Washington, 4225 Roosevelt Way NE #100, Seattle, WA 98105-6099. E-mail:cjo{at}u.washington.edu

  • ↵1 This work was supported by Grant GM 32281 from the National Institute of General Medical Sciences and by National Institute of Environmental Health Sciences Center Grant ES07733. B.S. was a recipient of a Swiss National Research Foundation fellowship. C.J.O. is a Burroughs Wellcome Fund Toxicology Scholar.

  • ↵2 Present address: Nestec Ltd Research Center, Vers-chez-les-Blanc, P.O. Box 44, CH-1000 Lausanne 26, Switzerland.

  • Abbreviations:
    CNS
    central nervous system
    P450
    cytochrome P450
    RT-PCR
    reverse transcription-polymerase chain reaction
    EH
    microsomal epoxide hydrolase
    PB
    phenobarbital
    QC
    quantitative competitive
    DPH
    diphenylhydantoin
    AMI
    amitryptiline
    DDT
    dichlorodiphenyltrichloroethane
    TSO
    trans-stilbene oxide
    DAS
    diallyl sulfide
    rcRNA
    recombinant competitive RNA
    FP
    forward primer
    RP
    reverse primer
    • Received January 7, 2000.
    • Accepted May 11, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Activation of Cytochrome P450 Gene Expression in the Rat Brain by Phenobarbital-Like Inducers

Benoît Schilter, Mark R. Andersen, Chetana Acharya and Curtis J. Omiecinski
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 916-922;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Activation of Cytochrome P450 Gene Expression in the Rat Brain by Phenobarbital-Like Inducers

Benoît Schilter, Mark R. Andersen, Chetana Acharya and Curtis J. Omiecinski
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 916-922;
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