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Research ArticleArticle

The Role of Conjugation in Hepatotoxicity of Troglitazone in Human and Porcine Hepatocyte Cultures

Vsevolod E. Kostrubsky, Jacqueline F. Sinclair, Vinod Ramachandran, Raman Venkataramanan, Yuan Hua Wen, Erick Kindt, Vladimir Galchev, Kelly Rose, Michael Sinz and Stephen C. Strom
Drug Metabolism and Disposition October 2000, 28 (10) 1192-1197;
Vsevolod E. Kostrubsky
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Jacqueline F. Sinclair
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Vinod Ramachandran
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Raman Venkataramanan
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Yuan Hua Wen
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Erick Kindt
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Vladimir Galchev
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Kelly Rose
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Michael Sinz
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Stephen C. Strom
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Abstract

In primary human and porcine hepatocyte cultures, we investigated the relationship between metabolism and cytotoxicity of troglitazone. Treatment of human hepatocytes for 2 h with 10, 20, 25, 35, and 50 μM troglitazone in protein-free medium resulted in concentration-dependent decreases in total protein synthesis. Decreases at 10 and 20 μM were reversible by 24 h, however protein synthesis did not recover at concentrations ≥25 μM. Troglitazone at 50 μM caused cellular death. In porcine hepatocytes, 100 μM troglitazone was lethal, whereas at 50 μM, protein synthesis completely recovered by 24 h. Recovery in protein synthesis was associated with metabolism of parent drug, whereas toxicity correlated (r2 = 0.82) with accumulation of unmetabolized troglitazone. By 1 h, in human hepatocytes, troglitazone was metabolized to similar amounts of sulfate and quinone metabolites with little glucuronide detected. In contrast, porcine hepatocytes metabolized troglitazone to the similar amounts of glucuronide and the quinone metabolites with little sulfate detected. Exposure of human hepatocytes to a combination of 10 μM troglitazone and 10 μM 2,4-dichloro-4-nitrophenol resulted in a 70% decrease in protein synthesis, associated with 90% inhibition in the formation of troglitazone sulfate, a 4-fold increase in unmetabolized troglitazone, and no effect on formation of the quinone metabolite. Treatment with a combination of acetaminophen or phenobarbital with 20 μM troglitazone resulted in sustained decrease in protein synthesis associated with inhibition of sulfation and accumulation of troglitazone. These results suggest that inhibition of troglitazone sulfation may result in increased hepatotoxicity due to exposure to parent drug, or increased metabolism by alternate pathways.

Footnotes

  • Send reprint requests to: Dr. V. Kostrubsky, Pfizer Global Research & Development, Department of Drug Safety Evaluation, 2800 Plymouth Rd., Ann Arbor, MI 48105. E-mail:vsevolod.kostrubsky{at}pfizer.com

  • Abbreviations used are::
    TRO
    troglitazone
    APAP
    acetaminophen
    PB
    phenobarbital
    DCNP
    2,6-dichloro-4-nitrophenol
    PCP
    pentachlorophenol
    DMSO
    dimethyl sulfoxide
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    • Received March 20, 2000.
    • Accepted June 30, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (10)
Drug Metabolism and Disposition
Vol. 28, Issue 10
1 Oct 2000
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Research ArticleArticle

The Role of Conjugation in Hepatotoxicity of Troglitazone in Human and Porcine Hepatocyte Cultures

Vsevolod E. Kostrubsky, Jacqueline F. Sinclair, Vinod Ramachandran, Raman Venkataramanan, Yuan Hua Wen, Erick Kindt, Vladimir Galchev, Kelly Rose, Michael Sinz and Stephen C. Strom
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1192-1197;

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Research ArticleArticle

The Role of Conjugation in Hepatotoxicity of Troglitazone in Human and Porcine Hepatocyte Cultures

Vsevolod E. Kostrubsky, Jacqueline F. Sinclair, Vinod Ramachandran, Raman Venkataramanan, Yuan Hua Wen, Erick Kindt, Vladimir Galchev, Kelly Rose, Michael Sinz and Stephen C. Strom
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1192-1197;
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