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Research ArticleArticle

CYP2E1 Metabolism of Styrene Involves Allostery

Jessica H. Hartman, Gunnar Boysen and Grover P. Miller
Drug Metabolism and Disposition October 2012, 40 (10) 1976-1983; DOI: https://doi.org/10.1124/dmd.112.046698
Jessica H. Hartman
Departments of Biochemistry and Molecular Biology (J.H.H., G.P.M.) and Occupational Health and Safety (G.B.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Gunnar Boysen
Departments of Biochemistry and Molecular Biology (J.H.H., G.P.M.) and Occupational Health and Safety (G.B.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Grover P. Miller
Departments of Biochemistry and Molecular Biology (J.H.H., G.P.M.) and Occupational Health and Safety (G.B.), University of Arkansas for Medical Sciences, Little Rock, Arkansas
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Abstract

We are the first to report allosterism during styrene oxidation by recombinant CYP2E1 and human liver microsomes. At low styrene concentrations, oxidation is inefficient because of weak binding to CYP2E1 (Ks = 830 μM). A second styrene molecule then binds CYP2E1 with higher affinity (Kss = 110 μM) and significantly improves oxidation to achieve a kcat of 6.3 nmol · min−1 · nmol CYP2E1−1. The transition between these metabolic cycles coincides with reported styrene concentrations in blood from exposed workers; thus, this CYP2E1 mechanism may be relevant in vivo. Scaled modeling of the in vitro-positive allosteric mechanism for styrene metabolism to its in vivo clearance led to significant deviations from the traditional model based on Michaelis-Menten kinetics. Low styrene levels were notably much less toxic than generally assumed. We interrogated the allosteric mechanism using the CYP2E1-specific inhibitor and drug 4-methylpyrazole, which we have shown binds two CYP2E1 sites. From the current studies, styrene was a positive allosteric effector on 4-methylpyrazole binding, based on a 10-fold increase in 4-methylpyrazole binding affinity from Ki 0.51 to Ksi 0.043 μM. The inhibitor was a negative allosteric effector on styrene oxidation, because kcat decreased 6-fold to 0.98 nmol · min−1 · nmol CYP2E1−1. Consequently, mixtures of styrene and other molecules can induce allosteric effects on binding and metabolism by CYP2E1 and thus mitigate the efficiency of their metabolism and corresponding effects on human health. Taken together, our elucidation of mechanisms for these allosteric reactions provides a powerful tool for further investigating the complexities of CYP2E1 metabolism of drugs and pollutants.

Footnotes

  • This work was supported in part by the National Institutes of Health National Center for Research Resources [Grant P20-RR-16460] (IDeA Networks of Biomedical Research Excellence Program; to J.H.H. and G.P.M.); the Summer Undergraduate Research Fellowship sponsored by the Biochemistry and Molecular Biology Department at the University of Arkansas for Medical Sciences (to J.H.H. and G.P.M.); a bridging grant from the University of Arkansas for Medical Sciences (to G.P.M.); and the Arkansas Tobacco Settlement Proceeds Act of 2000 (to G.B).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.046698.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    HLM
    human liver microsomes
    HPLC
    high-performance liquid chromatography
    ES
    enzyme-substrate
    ESS
    enzyme-substrate-substrate
    ESI
    enzyme-substrate-inhibitor
    AIC
    Akaike's information criterion.

  • Received May 15, 2012.
  • Accepted July 17, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (10)
Drug Metabolism and Disposition
Vol. 40, Issue 10
1 Oct 2012
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Research ArticleArticle

CYP2E1 METABOLISM OF STYRENE INVOLVES ALLOSTERIC MECHANISM

Jessica H. Hartman, Gunnar Boysen and Grover P. Miller
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1976-1983; DOI: https://doi.org/10.1124/dmd.112.046698

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Research ArticleArticle

CYP2E1 METABOLISM OF STYRENE INVOLVES ALLOSTERIC MECHANISM

Jessica H. Hartman, Gunnar Boysen and Grover P. Miller
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1976-1983; DOI: https://doi.org/10.1124/dmd.112.046698
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