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Research ArticleArticle

Differential Maintenance of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Anthony B. Renwick, Patricia S. Watts, Robert J. Edwards, Paula T. Barton, Isabelle Guyonnet, Roger J. Price, J. Michael Tredger, Olavi Pelkonen, Alan R. Boobis and Brian G. Lake
Drug Metabolism and Disposition October 2000, 28 (10) 1202-1209;
Anthony B. Renwick
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Patricia S. Watts
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Robert J. Edwards
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Paula T. Barton
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Isabelle Guyonnet
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Roger J. Price
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J. Michael Tredger
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Olavi Pelkonen
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Alan R. Boobis
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Brian G. Lake
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Abstract

The maintenance of the major hepatic cytochrome P450 (CYP) enzymes has been studied in precision-cut human liver slices cultured for up to 72 h in supplemented RPMI 1640 medium. The relative apoprotein levels of 11 CYP enzymes were determined using a panel of antipeptide antibodies. In addition, 7-ethoxyresorufin O-deethylase, tolbutamide methylhydroxylase, debrisoquine 4-hydroxylase, and testosterone 6β-hydroxylase activities were determined as enzymatic markers for CYP1A2, CYP2C9, CYP2D6, and CYP3A4, respectively. There was a large variation in the rate of decline of different CYP levels with time in culture. Based on the rate of decrease, CYP enzymes could be separated into two groups, with CYP2C9, CYP2D6, CYP3A4, and CYP4A11 being relatively stable (half-lives between 70 and 104 h), compared with CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, and CYP3A5, which were relatively unstable (half-lives between 23 and 36 h). Enzyme activities decreased at rates similar to those of their corresponding apoproteins. There was also a large difference in the stability of individual CYP enzymes from different liver donors, particularly for the most rapidly declining CYP enzymes. Similar losses of CYP enzymes were found when human liver slices were cultured in supplemented Williams' medium E for 72 h, except that CYP2E1 apoprotein levels were better maintained. Because of the variable decreases of CYP enzymes, xenobiotic metabolism studies are best performed with freshly cut rather than cultured human liver slices.

Footnotes

  • Send reprint requests to: Dr. Brian G. Lake, TNO BIBRA International Ltd, Woodmansterne Rd., Carshalton, Surrey, SM5 4DS, UK. E-mail: blake{at}bibra.co.uk

  • The provision of financial support by a grant from the Commission of the European Communities (Project “Eurocyp”, BIOMED Contract No. BMH4-CT96-0254) and a Realizing Our Potential Award from the Medical Research Council are gratefully acknowledged.

  • Abbreviation used is::
    CYP
    cytochrome P450
    • Received May 4, 1999.
    • Accepted June 20, 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

Differential Maintenance of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Anthony B. Renwick, Patricia S. Watts, Robert J. Edwards, Paula T. Barton, Isabelle Guyonnet, Roger J. Price, J. Michael Tredger, Olavi Pelkonen, Alan R. Boobis and Brian G. Lake
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1202-1209;

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Research ArticleArticle

Differential Maintenance of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Anthony B. Renwick, Patricia S. Watts, Robert J. Edwards, Paula T. Barton, Isabelle Guyonnet, Roger J. Price, J. Michael Tredger, Olavi Pelkonen, Alan R. Boobis and Brian G. Lake
Drug Metabolism and Disposition October 1, 2000, 28 (10) 1202-1209;
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