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Research ArticleTOXICOLOGY

Possible Mechanism of Hepatocyte Injury Induced by Diphenylamine and Its Structurally Related Nonsteroidal Anti-Inflammatory Drugs

Yasuhiro Masubuchi, Shoko Yamada and Toshiharu Horie
Journal of Pharmacology and Experimental Therapeutics March 2000, 292 (3) 982-987;
Yasuhiro Masubuchi
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Shoko Yamada
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Toshiharu Horie
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Abstract

Diphenylamine is a common structure of nonsteroidal anti-inflammatory drugs (NSAIDs) to uncouple mitochondrial oxidative phosphorylation and to cause a decrease in hepatocellular ATP content and hepatocyte injury. The mechanism for acute cell injury induced by diphenylamine and its structurally related NSAIDs was investigated with rat liver mitochondria and freshly isolated hepatocytes, focusing on the relation to the uncoupling of oxidative phosphorylation. Incubation of mitochondria with diphenylamine as well as mefenamic acid and diclofenac caused pseudoenergetic mitochondrial swelling, indicating that these compounds induce mitochondrial membrane permeability transition. Diphenylamine also caused changes in safranine-binding spectra to mitochondria that was energized by succinate oxidation. This spectral shift indicates the loss of mitochondrial membrane potentials, which is known as one of the characteristics for uncouplers of oxidative phosphorylation, and also was caused by mefenamic acid and diclofenac. Incubation of hepatocytes with mefenamic acid, diclofenac, and diphenylamine diminished cellular ATP content, followed by leakage of lactose dehydrogenase from hepatocytes. Fructose, a lowKm substrate for glycolysis, partially protected against the ATP depletion and hepatocyte injury induced by these compounds. Further addition of oligomycin, which blocks ATPase, pronounced the protection against cell injury. These results suggested that decreases in cellular ATP content, mainly caused by uncoupling of mitochondrial oxidative phosphorylation, were responsible for acute hepatocyte injury induced by diphenylamine and structurally related NSAIDs.

Footnotes

  • Send reprint requests to: Toshiharu Horie, Ph.D., Laboratory of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Chiba University, 1–33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. E-mail: horieto{at}p.chiba-u.ac.jp

  • Abbreviations:
    NSAID
    nonsteroidal anti-inflammatory drug
    LDH
    lactate dehydrogenase
    MPT
    mitochondrial permeability transition
    • Received July 29, 1999.
    • Accepted November 11, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 3
1 Mar 2000
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Research ArticleTOXICOLOGY

Possible Mechanism of Hepatocyte Injury Induced by Diphenylamine and Its Structurally Related Nonsteroidal Anti-Inflammatory Drugs

Yasuhiro Masubuchi, Shoko Yamada and Toshiharu Horie
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 982-987;

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Research ArticleTOXICOLOGY

Possible Mechanism of Hepatocyte Injury Induced by Diphenylamine and Its Structurally Related Nonsteroidal Anti-Inflammatory Drugs

Yasuhiro Masubuchi, Shoko Yamada and Toshiharu Horie
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 982-987;
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