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Evaluation of Atypical Cytochrome P450 Kinetics with Two-Substrate Models:  Evidence That Multiple Substrates Can Simultaneously Bind to Cytochrome P450 Active Sites

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Center for Clinical Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15217, Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania 19486, Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia 26506
Cite this: Biochemistry 1998, 37, 12, 4137–4147
Publication Date (Web):March 3, 1998
https://doi.org/10.1021/bi9715627
Copyright © 1998 American Chemical Society

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    Abstract

    Some cytochrome P450 catalyzed reactions show atypical kinetics, and these kinetic processes can be grouped into five categories:  activation, autoactivation, partial inhibition, substrate inhibition, and biphasic saturation curves. A two-site model in which the enzyme can bind two substrate molecules simultaneously is presented which can be used to describe all of these observed kinetic properties. Sigmoidal kinetic characteristics were observed for carbamazepine metabolism by CYP3A4 and naphthalene metabolism by CYPs 2B6, 2C8, 2C9, and 3A5 as well as dapsone metabolism by CYP2C9. Naphthalene metabolism by CYP3A4 and naproxen metabolism by CYP2C9 demonstrated nonhyperbolic enzyme kinetics suggestive of a low Km, low Vmax component for the first substrate molecule and a high Km, high Vmax component for the second substrate molecule. 7,8-Benzoflavone activation of phenanthrene metabolism by CYP3A4 and dapsone activation of flurbiprofen and naproxen metabolism by CYP2C9 were also observed. Furthermore, partial inhibition of 7,8-benzoflavone metabolism by phenanthrene was observed. These results demonstrate that various P450 isoforms may exhibit atypical enzyme kinetics depending on the substrate(s) employed and that these results may be explained by a model which includes simultaneous binding of two substrate molecules in the active site.

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     Supported by NSF Grant OSR-9450578 and NIH Grants NO1-DK-6-2274 and GM32165.

    *

     To whom correspondence should be addressed at the Center for Clinical Pharmacology, 623 Scaife Hall, University of Pittsburgh Medical Center, Pittsburgh, PA 15213.

     University of Pittsburgh.

    §

     Merck Research Laboratories.

     University of Washington.

     National Cancer Institute.

    #

     West Virginia University.

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