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Cooperativity in Oxidations Catalyzed by Cytochrome P450 3A4

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Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
Cite this: Biochemistry 1997, 36, 2, 370–381
Publication Date (Web):January 14, 1997
https://doi.org/10.1021/bi962359z
Copyright © 1997 American Chemical Society

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    Abstract

    Cytochrome P450 (P450) 3A4 is the most abundant human P450 and oxidizes a diversity of substrates, including various drugs, steroids, carcinogens, and macrolide natural products. In some reactions, positive cooperativity has been reported in microsomal studies. Flavonoids, e.g., 7,8-benzoflavone (α-naphthoflavone, αNF), have been shown to stimulate some reactions but not others. In systems containing purified recombinant bacterial P450 3A4, positive cooperativity was seen in oxidations of several substrates, including testosterone, 17β-estradiol, amitriptyline, and most notably aflatoxin (AF) B1. With these and other reactions, αNF typically reduced cooperativity (i.e., the n value in a Hill plot) while either stimulating or inhibiting reactions. With the substrate AFB1, αNF both stimulated 8,9-epoxidation and inhibited 3α-hydroxylation. The same patterns were seen with AFB1 in a fused P450 3A4−NADPH-P450 reductase protein. αNF did not alter patterns of activity plotted as a function of NADPH-P450 reductase concentration in systems containing the individual proteins. The patterns of AFB1 oxidation to the two products were modified considerably in systems in which NADPH-P450 reductase was replaced with a flavodoxin or ferredoxin system, iodosylbenzene, or cumene hydroperoxide. AFB2, which differs from AFB1 only in the presence of a saturated 8,9-bond, was not oxidized by P450 3A4 but could inhibit AFB1 oxidation. These and other results are considered in the context of several possible models. The results support a model in which an allosteric site is involved, although the proximity of this putative site to the catalytic site cannot be ascertained as of yet. In order to explain the differential effects of αNF and reduction systems on the two oxidations of AFB1, a model is presented in which binding of substrate in a particular conformation can facilitate oxygen activation to enhance catalysis.

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     This research was supported in part by Public Health Service Grants R35 CA44353 and P30 ES00267.

     Current address:  National Research Institute of Chinese Medicine, 155-1, Li-Nong Street, Section 2, Taipei 11221, Taiwan, Republic of China.

    §

     Current address:  Toxicology Research Center, Korean Research Institute of Chemical Technology, 100 Jang-dong, Yuseong-gu, Taejon, South Korea.

    *

     Address correspondence to this author. Telephone: (615) 322-2261. Fax:  (615) 322-3141. E-mail:  guengerich@ toxicology.mc.vanderbilt.edu.

     Abstract published in Advance ACS Abstracts, December 15, 1996.

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