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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Role of Intestinal Cytochrome P450 Enzymes in Diclofenac-Induced Toxicity in the Small Intestine

Yi Zhu and Qing-Yu Zhang
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 362-370; DOI: https://doi.org/10.1124/jpet.112.198077
Yi Zhu
Laboratory of Molecular Toxicology, Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York
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Qing-Yu Zhang
Laboratory of Molecular Toxicology, Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York
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Abstract

The aim of this study was to determine the role of small intestinal (SI) cytochrome P450 (P450) enzymes in the metabolic activation of diclofenac (DCF), a widely used nonsteroidal anti-inflammatory drug, and DCF-induced intestinal toxicity. DCF induces intestinal ulcers in humans and mice, but the underlying mechanisms, including the necessity for drug bioactivation in the target tissues and the sources and identities of reactive intermediates, are not fully understood. We found that the number of DCF-induced (at 50 mg/kg p.o.) intestinal ulcers was significantly smaller in an intestinal epithelium (IE)-specific P450 reductase (CPR) knockout (IE-Cpr-null) mouse model, which has little P450 activity in the IE, than in wild-type (WT) mice, determined at 14 h after DCF administration. The involvement of intestinal P450 enzymes was confirmed by large reductions (>80–90%) in the rates of in vitro formation, in SI microsomal reactions, of hydroxylated DCF metabolites and reactive intermediates, trapped as DCF-glutathione (GSH) conjugates, in the IE-Cpr-null, compared with WT mice. The SI levels of DCF-GSH conjugates (at 4 h after dosing) and DCF-protein adducts (at 14 h after dosing) were significantly lower in IE-Cpr-null than in WT mice. In additional experiments, we found that pretreatment of mice with grapefruit juice, which is known to inhibit SI P450 activity, ameliorated DCF-induced intestinal toxicity in WT mice. Our results not only strongly support the notion that SI P450 enzymes play an important role in DCF-induced intestinal toxicity, but also illustrate the possibility of preventing DCF-induced intestinal toxicity through dietary intervention.

Footnotes

  • This study was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM082978].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.198077.

  • ABBREVIATIONS:

    DCF
    diclofenac
    DCF-D4
    deuterated diclofenac
    4′-OH-DCF
    4′-hydroxy-diclofenac
    5-OH-DCF
    5-hydroxy-diclofenac
    DCF-G
    diclofenac acyl-glucuronide
    P450
    cytochrome P450
    CPR
    cytochrome P450 reductase
    WT
    wild type
    SI
    small intestine
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    IE
    intestinal epithelium
    GFJ
    grapefruit juice
    GSH
    glutathione
    UGT
    UDP-glucuronosyltransferase
    UDPGA
    UDP-glucuronic acid.

  • Received July 5, 2012.
  • Accepted August 3, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Diclofenac-Induced Intestinal Toxicity

Yi Zhu and Qing-Yu Zhang
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 362-370; DOI: https://doi.org/10.1124/jpet.112.198077

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Diclofenac-Induced Intestinal Toxicity

Yi Zhu and Qing-Yu Zhang
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 362-370; DOI: https://doi.org/10.1124/jpet.112.198077
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