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Research ArticleArticle

Human Cytochrome P450 3A4-Catalyzed Testosterone 6β-Hydroxylation and ErythromycinN-Demethylation

Competition During Catalysis

Regina W. Wang, Deborah J. Newton, Tad D. Scheri and Anthony Y. H. Lu
Drug Metabolism and Disposition April 1997, 25 (4) 502-507;
Regina W. Wang
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Deborah J. Newton
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Tad D. Scheri
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Anthony Y. H. Lu
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Competition During Catalysis

Abstract

Cytochrome P450 3A4 is known to catalyze the metabolism of both endogenous substrates (such as the 6β-hydroxylation of testosterone) and many important therapeutic agents, including theN-demethylation of erythromycin. However, erythromycin and testosterone have been reported to have little or no effect on the metabolism of each other by recombinant CYP3A4. In an effort to understand the basis of these observations, we studied theN-demethylation of erythromycin and the 6β-hydroxylation of testosterone in human liver microsomes and in microsomes from cells containing recombinant human CYP3A4 and P450 reductase under a variety of experimental conditions. In both human liver microsomal and recombinant CYP3A4 systems, erythromycin inhibited testosterone 6β-hydroxylation in a concentration dependent manner, and vice versa. However, the inhibition mechanism was complex. At low substrate concentrations, testosterone and erythromycin acted as competitive inhibitors to each other. Under these experimental conditions, an apparent competitive inhibition of testosterone 6β-hydroxylation by erythromycin was observed, withKi values similar to that of theKm values for erythromycin. When the rates of testosterone 6β-hydroxylation and erythromycinN-demethylation were determined in microsomal incubations containing both substrates at lower concentrations, the observed rates for each reaction were in good agreement with the calculated rates based on the rate equation describing simultaneous metabolism of two substrates by a single enzyme. However, at high substrate concentrations, the kinetic results could be best explained by a mechanism involving partial competitive inhibition. We conclude from these studies that testosterone and erythromycin mutually inhibit the metabolism of each other, consistent with the fact that CYP 3A4 catalyzes the metabolism of both substrates.

Footnotes

  • Send reprint requests to: Ms. Regina W. Wang, Department of Drug Metabolism, RY 80-A12, Merck Research Laboratories, P.O. BOX 2000, Rahway, NJ 07065.

  • Abbreviations used are::
    CYP3A4
    cytochrome P450 3A4
    CYP3A4/OR
    CYP3A4 and NADPH-cytochrome P450 reductase
    • Received October 16, 1996.
    • Accepted January 20, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 4
1 Apr 1997
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Research ArticleArticle

Human Cytochrome P450 3A4-Catalyzed Testosterone 6β-Hydroxylation and ErythromycinN-Demethylation

Regina W. Wang, Deborah J. Newton, Tad D. Scheri and Anthony Y. H. Lu
Drug Metabolism and Disposition April 1, 1997, 25 (4) 502-507;

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Research ArticleArticle

Human Cytochrome P450 3A4-Catalyzed Testosterone 6β-Hydroxylation and ErythromycinN-Demethylation

Regina W. Wang, Deborah J. Newton, Tad D. Scheri and Anthony Y. H. Lu
Drug Metabolism and Disposition April 1, 1997, 25 (4) 502-507;
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