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Research ArticleArticle

Concurrent Flavin-Containing Monooxygenase Down-Regulation and Cytochrome P-450 Induction by Dietary Indoles in Rat: Implications for Drug-Drug Interaction

Sirinmas Katchamart, David M. Stresser, Shangara S. Dehal, David Kupfer and David E. Williams
Drug Metabolism and Disposition August 2000, 28 (8) 930-936;
Sirinmas Katchamart
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David M. Stresser
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Shangara S. Dehal
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David Kupfer
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David E. Williams
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Abstract

Our laboratory has previously shown that dietary administration of indole-3-carbinol (I3C) to male Fischer 344 rats has the very unusual property of inducing hepatic levels of a number of cytochrome P450s (CYPs), especially CYP1A1, while markedly inhibiting the levels of flavin-containing monooxygenase (FMO) 1 protein and its catalytic activity. We hypothesized that rats fed I3C or 3,3′-diindolylmethane (DIM), one of its major acid condensation products formed in vivo, should exhibit a marked shift in the metabolic profiles of drugs or xenobiotics that are substrates for both monooxygenase systems. Male rats were fed AIN-76A powdered diets containing 0, 1000, or 2500 ppm I3C or DIM for 4 weeks. Dietary I3C and DIM reduced FMO1 protein levels (8% reduction with I3C and 84% with DIM at 1000 ppm, and 90% reduction with I3C and 97% with DIM at 2500 ppm) in hepatic microsomes. The ratio of FMO (N-oxygenation)- to CYP (N-demethylation)-mediated metabolism ofN,N-dimethylaniline decreased in liver microsomes from I3C- or DIM-fed rats from near unity to 0.02 at the highest dietary doses. FMO-mediated N-oxygenation (nicotine N-1′-oxide) was decreased, whereas CYP-mediated (nornicotine and nicotine Δ 1,5-iminium ion) metabolism of nicotine was unchanged in liver microsomes from rats fed I3C or DIM. Similarly, the ratio of FMO to CYP metabolites of tamoxifen decreased due to a reduction in N-oxygenation. This study demonstrates alteration of FMO- and CYP-mediated drug metabolism in vitro by dietary I3C or DIM and suggests the potential for altered toxicity of tamoxifen and nicotine in vivo.

Footnotes

  • Send reprint requests to: Dr. David E. Williams, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-6602. E-mail:David.Williams{at}orst.edu

  • ↵1 A portion of this work was presented at the Society of Toxicology annual meeting, 1999, New Orleans, LA (abstract 1068).

  • This work was supported by U.S. Public Health Service Grants HL38650 (D.E.W.) and ES00834 (D.K.).

  • Abbreviations used are::
    I3C
    indole-3-carbinol
    CYP
    cytochrome P450
    FMO
    flavin-containing monooxygenase
    DIM
    3,3′-diindolylmethane
    DMA
    N,N-dimethylaniline
    ICZ
    indole[3,2-b]carbazole
    • Received January 28, 2000.
    • Accepted April 14, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (8)
Drug Metabolism and Disposition
Vol. 28, Issue 8
1 Aug 2000
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Research ArticleArticle

Concurrent Flavin-Containing Monooxygenase Down-Regulation and Cytochrome P-450 Induction by Dietary Indoles in Rat: Implications for Drug-Drug Interaction

Sirinmas Katchamart, David M. Stresser, Shangara S. Dehal, David Kupfer and David E. Williams
Drug Metabolism and Disposition August 1, 2000, 28 (8) 930-936;

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Research ArticleArticle

Concurrent Flavin-Containing Monooxygenase Down-Regulation and Cytochrome P-450 Induction by Dietary Indoles in Rat: Implications for Drug-Drug Interaction

Sirinmas Katchamart, David M. Stresser, Shangara S. Dehal, David Kupfer and David E. Williams
Drug Metabolism and Disposition August 1, 2000, 28 (8) 930-936;
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