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Research ArticleArticle

Structural Requirements for the Hepatotoxicity of Nonsteroidal Anti-inflammatory Drugs in Isolated Rat Hepatocytes

Yasuhiro Masubuchi, Haruka Saito and Toshiharu Horie
Journal of Pharmacology and Experimental Therapeutics October 1998, 287 (1) 208-213;
Yasuhiro Masubuchi
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Haruka Saito
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Toshiharu Horie
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Abstract

Hepatotoxicity is one of the common side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). We investigated the cytotoxicity of 18 acidic NSAIDs (3 salicylic acids, 3 anthranilic acids, 6 arylacetic acids, 6 arylpropionic acids) to freshly isolated rat hepatocytes as assessed by the NSAID-induced leakage of lactate dehydrogenase (LDH) in order to determine structural requirements for the direct hepatotoxicity of the NSAIDs. Diflunisal (salicylic acids), flufenamic acid, mefenamic acid, tolfenamic acid (anthranilic acids), diclofenac, indomethacin, acemetacin (arylacetic acids) and flurbiprofen (arylpropionic acids) caused significant LDH leakage, indicating that substituent position of a carboxyl group does not relate to the hepatotoxicity of the NSAIDs. Because the cytotoxic NSAIDs were of two types as classified by their “skeleton,” diphenyl and diphenylamine, we tested the cytotoxicity of the compounds. Diphenyl did not cause LDH leakage, but diflunisal, which has the diphenyl structure, was cytotoxic. On the other hand, diphenylamine induced LDH leakage to the same degree as diclofenac, which has the diphenylamine structure. Therefore, diphenylamine itself was suggested to be responsible for the cytotoxicity of diclofenac and anthranilic acids, whereas a substituted group(s) in addition to diphenyl structure seems to be important for diflunisal cytotoxicity. All of the cytotoxic NSAIDs and diphenylamine extensively decreased hepatocellular ATP content, whereas the noncytotoxic NSAID did not, indicating that the NSAID-induced decrease in ATP, probably by their uncoupling effects on mitochondrial oxidative phosphorylation, is involved in the hepatotoxicity of the 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

  • ↵1 This work was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science and Culture (No .09470491 and No. 09771964) and Hoansha Foundation.

  • Abbreviations:
    NSAID
    nonsteroidal anti-inflammatory drug
    LDH
    lactate dehydrogenase
    DMSO
    dimethylsulfoxide
    P450
    cytochrome P450
    UDPGA
    UDP-glucuronic acid
    UDPGT
    UDP-glucuronosyltransferase
    • Received January 12, 1998.
    • Accepted June 1, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 1
1 Oct 1998
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Research ArticleArticle

Structural Requirements for the Hepatotoxicity of Nonsteroidal Anti-inflammatory Drugs in Isolated Rat Hepatocytes

Yasuhiro Masubuchi, Haruka Saito and Toshiharu Horie
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 208-213;

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Research ArticleArticle

Structural Requirements for the Hepatotoxicity of Nonsteroidal Anti-inflammatory Drugs in Isolated Rat Hepatocytes

Yasuhiro Masubuchi, Haruka Saito and Toshiharu Horie
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 208-213;
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