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Research ArticleArticle

Diclofenac Toxicity to Hepatocytes: A Role for Drug Metabolism in Cell Toxicity

Roque Bort, Xavier Ponsoda, Ramiro Jover, M. José Gómez-Lechón and José V. Castell
Journal of Pharmacology and Experimental Therapeutics January 1999, 288 (1) 65-72;
Roque Bort
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Xavier Ponsoda
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Ramiro Jover
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M. José Gómez-Lechón
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José V. Castell
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Abstract

Diclofenac, a 2-arylacetic acid, nonsteroidal anti-inflammatory drug, has been reported to cause adverse hepatic effects in certain individuals. To discriminate among possible mechanisms of hepatotoxicity, we examined the effects of diclofenac on human and rat hepatocytes and hepatic cell lines (HepG2, FaO), investigated the major biochemical events in the course of diclofenac cytotoxicity (calcium homeostasis, lipid peroxidation, and mitochondrial dysfunction), and investigated whether cytotoxicity could be related to drug metabolism by cytochrome P-450. Acute diclofenac-induced toxicity in hepatocytes was preluded by a decrease in ATP levels, whereas no significant oxidative stress (decrease in glutathione and lipid peroxidation) or increase in intracellular calcium concentration could be observed at early incubation stages. Diclofenac was more cytotoxic to drug metabolizing cells (rat and human primary cultured hepatocytes) than to nonmetabolizing cell lines (HepG2, FaO). Despite the fact that diclofenac itself was effective in impairing ATP synthesis by mitochondria, we found evidence that toxicity was also related to drug metabolism and was reduced by the addition of cytochrome P-450 inhibitors (proadifen and ketoconazole) to culture medium. The in vitro cytotoxicity correlated well with the formation by hepatocytes of 5-hydroxydiclofenac and, in particular,N,5-dihydroxydiclofenac, a minor metabolite first characterized in this article. Hepatic microsomes showed the ability to both oxidize 5-hydroxydiclofenac toN,5-dihydroxydiclofenac and back reduce the latter to 5-hydroxydiclofenac with the consumption of NADPH. The experimental results suggest that the toxic effect of diclofenac on hepatocytes may be caused by drug-induced mitochondrial impairment, together with a futile consumption of NADPH.

Footnotes

  • Send reprint requests to: Dr. José V. Castell, Unidad de Hepatologı́a Experimental. Centro de Investigación, Hospital Universitario “La Fe”, SVS. Avda. Campanar 21, E-46009 Valencia, Spain. E-mail:Jose.Castell{at}uv.es

  • ↵1 This study was supported, in part, by the BIOMED II Research Program of the European Union and the Fondo de Investigaciones Sanitarias, Spanish Ministry of Health. R.B. was recipient of a predoctoral fellowship from the Consellerı́a de Educación y Ciencia, Generalitat Valenciana.

  • Abbreviations:
    BHT
    buthylated hydroxytoluene
    BSO
    l-buthionine-[S,R]-sulfoximine
    CYP
    cytochrome P-450
    MDA
    malondialdehyde
    DEM
    maleic acid diethyl ester
    MTT
    3-[4,5-dimethylthiazol-2-yl]-3,5-diphenylformazan
    PBS
    phosphate-buffered saline
    4′-OHdic
    4′-hydroxydiclofenac
    5-OHdic
    5-hydroxydiclofenac
    N
    5-(OH)2dic,N,5-dihydroxydiclofenac
    [Ca++]i
    intracellular calcium
    GSH
    glutathione
    HPLC-MS
    high-performance liquid chromatography-mass spectrometry
    • Received April 8, 1998.
    • Accepted July 21, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 1
1 Jan 1999
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Research ArticleArticle

Diclofenac Toxicity to Hepatocytes: A Role for Drug Metabolism in Cell Toxicity

Roque Bort, Xavier Ponsoda, Ramiro Jover, M. José Gómez-Lechón and José V. Castell
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 65-72;

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Research ArticleArticle

Diclofenac Toxicity to Hepatocytes: A Role for Drug Metabolism in Cell Toxicity

Roque Bort, Xavier Ponsoda, Ramiro Jover, M. José Gómez-Lechón and José V. Castell
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 65-72;
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