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Research ArticleArticle

Induction of Rat Small Intestinal Cytochrome P-450 2J4

Qing-Yu Zhang, Xinxin Ding, Deborah Dunbar, Ling Cao and Laurence S. Kaminsky
Drug Metabolism and Disposition October 1999, 27 (10) 1123-1127;
Qing-Yu Zhang
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Xinxin Ding
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Deborah Dunbar
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Ling Cao
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Laurence S. Kaminsky
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Abstract

Cytochrome P-450 (CYP) 2J4 is a member of the recently identified CYP2J subfamily–part of the CYP superfamily–and is primarily expressed in rat small intestinal epithelium (enterocytes). Studies to determine small intestinal CYP2J4 inducibility by prototypic CYP inducers have been undertaken. Immunoblot analysis of enterocyte microsomes from rats treated with β-naphthoflavone, dexamethasone, or phenobarbital revealed unchanged, diminished, or slightly increased levels of CYP2J4 protein, respectively, relative to vehicle-treated rats, whereas rats treated with pyrazole (200 mg/kg) had 3- to 4-fold increased levels of CYP2J4. Pyrazole administration also increased CYP2J4 metabolic activity, as probed by retinoic acid formation from retinal, approximately 3-fold, and the activity was inhibited by 90% by a polyclonal anti-CYP2J4 antibody. CYP2J4 mRNA levels were increased 2.5-fold by pyrazole administration. The route of pyrazole administration–oral or i.p.–did not affect the extent or time course of intestinal CYP2J4 induction. However, at >300 mg/kg pyrazole, oral administration produced higher levels of CYP2J4 activity than i.p. administration. Pyrazole also produced increased hepatic and olfactory mucosal levels of CYP2J4. We speculate, based on our data and on published mechanisms of pyrazole induction, that pyrazole induces rat intestinal CYP2J4 by stabilization of mRNA primarily, and by stabilization of protein to a lesser extent. This study documents for the first time the induction of a CYP2J subfamily member by a xenobiotic and provides the basis for a mechanism by which xenobiotics could modulate biological processes.

Footnotes

  • Send reprint requests to: Laurence S. Kaminsky, Ph.D., New York State Department of Health, Wadsworth Center, P.O. Box 509, Albany, NY 12201-0509. E-mail: kaminsky{at}wadsworth.org

  • This work was supported in part by National Institutes of Health, U.S. Public Health Service Grants ES06256 (L.S.K.) and DC02640 (X.D.).

  • Abbreviations used are::
    CYP
    cytochrome P-450
    BNF
    β-naphthoflavone
    PB
    phenobarbital
    DEX
    dexamethasone
    TBST
    20 mM Tris-HCl (pH 7.4) containing 0.5 M NaCl and 0.05% Tween-20
    RA
    retinoic acid
    • Received April 15, 1999.
    • Accepted June 11, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (10)
Drug Metabolism and Disposition
Vol. 27, Issue 10
1 Oct 1999
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Research ArticleArticle

Induction of Rat Small Intestinal Cytochrome P-450 2J4

Qing-Yu Zhang, Xinxin Ding, Deborah Dunbar, Ling Cao and Laurence S. Kaminsky
Drug Metabolism and Disposition October 1, 1999, 27 (10) 1123-1127;

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Research ArticleArticle

Induction of Rat Small Intestinal Cytochrome P-450 2J4

Qing-Yu Zhang, Xinxin Ding, Deborah Dunbar, Ling Cao and Laurence S. Kaminsky
Drug Metabolism and Disposition October 1, 1999, 27 (10) 1123-1127;
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