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Research ArticleArticle

The Use of Human Hepatocyte Cultures to Study the Induction of Cytochrome P-450

Vsevolod E. Kostrubsky, Vinod Ramachandran, Raman Venkataramanan, Kenneth Dorko, James E. Esplen, Shimin Zhang, Jacqueline F. Sinclair, Steven A. Wrighton and Stephen C. Strom
Drug Metabolism and Disposition August 1999, 27 (8) 887-894;
Vsevolod E. Kostrubsky
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Vinod Ramachandran
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Raman Venkataramanan
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Kenneth Dorko
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James E. Esplen
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Shimin Zhang
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Jacqueline F. Sinclair
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Steven A. Wrighton
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Stephen C. Strom
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Abstract

We have previously reported that paclitaxel (Taxol) is a potent inducer of cytochrome P-450 (CYP) 3A protein and CYP3A mRNA in human hepatocyte cultures. Here we report that Taxol increased CYP3A-dependent testosterone 6β-hydroxylation in intact hepatocytes. This effect was concentration-dependent, with maximal increase in enzyme activity being observed at 10 μM Taxol. Treatment of hepatocyte cultures with concentrations of Taxol higher than 10 μM caused a dose-dependent decrease in testosterone 6β-hydroxylase activity, amount of CYP3A protein, and total protein synthesis. The maximal CYP3A activity detected after treatment with Taxol or rifampicin was similar in six separate human hepatocyte cultures, suggesting that the cultures have achieved a limit of maximally inducible CYP3A. The fold increase in enzyme activity, however, was different and was inversely related to the level of expression in untreated hepatocytes, with the greatest increases being observed in the hepatocytes that expressed the lowest basal level of CYP3A. Pretreatment of hepatocytes with triacetyloleandomycin resulted in a 90% inhibition of testosterone 6β-hydroxylase activity. Our results demonstrate the use of human hepatocyte cultures to investigate the induction of cytochrome P-450 by xenobiotics in intact cells and stress the importance of large dose-response studies as well as the need to assess toxicity in these investigations. The response to inducers of CYP3A activity were very consistent among different hepatocyte donors. Absolute values of testosterone 6β-hydroxylase activity did not vary more than 2- and 5-fold in induced and untreated hepatocytes, respectively.

Footnotes

  • Send reprint requests to: Dr. Stephen C. Strom, University of Pittsburgh Medical Center, Department of Pathology, S450 BST, Pittsburgh, PA 15261. E-mail: strom+{at}pitt.edu

  • This work was supported in part by the Anatomic Gift Foundation (K.D., J.E.E., S.C.S.), National Institutes of Health Grant NIH-N01-DK-9-2310 to SCS, and a postdoctoral fellowship from Lilly Research Laboratories (V.E.K.).

  • Abbreviations used are::
    CYP
    cytochrome P-450
    TAO
    triacetyloleandomycin
    HH
    human hepatocyte donor number
    • Received December 23, 1998.
    • Accepted April 30, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (8)
Drug Metabolism and Disposition
Vol. 27, Issue 8
1 Aug 1999
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Research ArticleArticle

The Use of Human Hepatocyte Cultures to Study the Induction of Cytochrome P-450

Vsevolod E. Kostrubsky, Vinod Ramachandran, Raman Venkataramanan, Kenneth Dorko, James E. Esplen, Shimin Zhang, Jacqueline F. Sinclair, Steven A. Wrighton and Stephen C. Strom
Drug Metabolism and Disposition August 1, 1999, 27 (8) 887-894;

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Research ArticleArticle

The Use of Human Hepatocyte Cultures to Study the Induction of Cytochrome P-450

Vsevolod E. Kostrubsky, Vinod Ramachandran, Raman Venkataramanan, Kenneth Dorko, James E. Esplen, Shimin Zhang, Jacqueline F. Sinclair, Steven A. Wrighton and Stephen C. Strom
Drug Metabolism and Disposition August 1, 1999, 27 (8) 887-894;
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