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Research ArticleArticle

Competition Between Cytochrome P-450 Isozymes for NADPH-Cytochrome P-450 Oxidoreductase Affects Drug Metabolism

Dongtao N. Li, Michael P. Pritchard, Steven P. Hanlon, Brian Burchell, C. Roland Wolf and Thomas Friedberg
Journal of Pharmacology and Experimental Therapeutics May 1999, 289 (2) 661-667;
Dongtao N. Li
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Michael P. Pritchard
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Steven P. Hanlon
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Brian Burchell
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C. Roland Wolf
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Thomas Friedberg
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Abstract

NADPH-cytochrome P-450 oxidoreductase (CPR) is essential for the catalytic activity of cytochrome P-450 (P-450). On a molar basis, the amount of P-450 exceeds that of CPR in human liver. In this study, we investigated whether drug-drug interactions can occur as a result of competition between P-450 isozymes for this ancillary protein. For this purpose, combinations of P-450 isozymes were coexpressed together with P-450 reductase in Escherichia coli. We show that testosterone inhibited the CYP2D6-mediated bufuralol 1′-hydroxylase activity in bacterial membranes containing both CYP2D6 and CYP3A4 but not in membranes containing CYP2D6 alone. Conversely, bufuralol inhibited the CYP3A4-mediated testosterone 6β-hydroxylase activity in bacterial membranes containing both CYP3A4 and CYP2D6 but not in membranes containing only CYP3A4. In each case, inhibition was seen even at a P-450 to P-450 reductase ratio of 1.9:1, which is more favorable than the ratio of 4 reported for human liver. The physiological significance of this mechanism was demonstrated by the observation that testosterone inhibited several prototypical P-450 enzyme activities, such as bufuralol 1′-hydroxylase, coumarin 7-hydroxylase, and 7-ethoxyresorufin O-dealkylase, in human liver microsomes, but not if tested against a panel of bacterial membranes containing the human P-450 isozymes that mainly catalyze these reactions.

Footnotes

  • Send reprint requests to: T. Friedberg, Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom. E-mail:t.h.friedburg{at}dundee.ac.uk

  • ↵1 This work was sponsored by the United Kingdom Biological Sciences Research Council, the United Kingdom Department of Trade and Industry and the LINK consortium of pharmaceutical companies: Astra, Glaxo-Wellcome, Janssen Pharmaceutica, Lilly, Novo-Nordisk, Parke-Davis, Pfizer, Roche Products, Sanofi, Servier, Smith-Kline Beecham, Wyeth-Ayerst and Zeneca.

  • Abbreviations:
    CPR
    NADPH-cytochrome P-450 oxidoreductase
    P-450
    cytochrome P-450
    IPTG
    isopropyl β-d-thiogalactopyranoside
    EROD
    7-ethoxyresorufinO-deethylase
    • Received July 7, 1998.
    • Accepted December 14, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 2
1 May 1999
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Research ArticleArticle

Competition Between Cytochrome P-450 Isozymes for NADPH-Cytochrome P-450 Oxidoreductase Affects Drug Metabolism

Dongtao N. Li, Michael P. Pritchard, Steven P. Hanlon, Brian Burchell, C. Roland Wolf and Thomas Friedberg
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 661-667;

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Research ArticleArticle

Competition Between Cytochrome P-450 Isozymes for NADPH-Cytochrome P-450 Oxidoreductase Affects Drug Metabolism

Dongtao N. Li, Michael P. Pritchard, Steven P. Hanlon, Brian Burchell, C. Roland Wolf and Thomas Friedberg
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 661-667;
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