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Research ArticleArticle

Mechanism-Based Inactivation of Rat Liver Cytochrome P-450 2B1 by 2-Methoxy-5-nitrobenzyl Bromide

Arthur P. Armstrong and Paul F. Hollenberg
Drug Metabolism and Disposition June 1999, 27 (6) 741-745;
Arthur P. Armstrong
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Paul F. Hollenberg
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Abstract

Mechanism-based inactivators serve as probes of enzyme mechanism, function, and structure. Koshland’s Reagent II (2-methoxy-5-nitrobenzyl bromide, KR-II) is a potential mechanism-based inactivator of enzymes that perform O-dealkylations. The major phenobarbital-inducible form of cytochrome P-450 in male rat liver microsomes, CYP2B1, is capable of catalyzingO-dealkylations. The interactions of KR-II with purified CYP2B1 in the reconstituted system containing P-450, NADPH:P-450 oxidoreductase, and sonicated dilaurylphosphatidyl choline were studied. The benzphetamine N-demethylase activity of CYP2B1 was inactivated by KR-II in a time- and NADPH-dependent manner, and the loss of activity followed pseudo-first-order kinetics. The inactivation also required KR-II, and the rate of activity loss was dependent on the concentration of KR-II in a saturable fashion. The inactivator concentration required for the half-maximal rate of inactivation (KI) was approximately 0.1 mM. The inactivation was not prevented by the addition of the nucleophiles dithiothreitol and glutathione, nor was it reversed by gel filtration. The present results demonstrate that KR-II is a mechanism-based inactivator of rat CYP2B1.

Footnotes

  • Send reprint requests to: Dr. Paul F. Hollenberg, Department of Pharmacology, Medical Science Research Building III, 1150 West Medical Center Dr., Ann Arbor, MI 48109-0632. E-mail:phollen{at}umich.edu

  • This research was supported in part by National Institutes of Health Grant CA16954.

  • Abbreviations used are::
    P-450
    cytochrome P-450
    CYP2B1
    the major form of cytochrome P-450 from phenobarbital-pretreated rats
    KR-I
    Koshland’s Reagent I
    KR-II
    Koshland’s Reagent II
    DLPC
    dilaurylphosphatidyl choline
    • Received July 22, 1998.
    • Accepted February 8, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (6)
Drug Metabolism and Disposition
Vol. 27, Issue 6
1 Jun 1999
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Research ArticleArticle

Mechanism-Based Inactivation of Rat Liver Cytochrome P-450 2B1 by 2-Methoxy-5-nitrobenzyl Bromide

Arthur P. Armstrong and Paul F. Hollenberg
Drug Metabolism and Disposition June 1, 1999, 27 (6) 741-745;

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Research ArticleArticle

Mechanism-Based Inactivation of Rat Liver Cytochrome P-450 2B1 by 2-Methoxy-5-nitrobenzyl Bromide

Arthur P. Armstrong and Paul F. Hollenberg
Drug Metabolism and Disposition June 1, 1999, 27 (6) 741-745;
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