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Rapid CommunicationShort Communication

Human Hepatic Cytochrome P450-Specific Metabolism of the Organophosphorus Pesticides Methyl Parathion and Diazinon

Corie A. Ellison, Yuan Tian, James B. Knaak, Paul J. Kostyniak and James R. Olson
Drug Metabolism and Disposition January 2012, 40 (1) 1-5; DOI: https://doi.org/10.1124/dmd.111.042572
Corie A. Ellison
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Yuan Tian
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James B. Knaak
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Paul J. Kostyniak
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James R. Olson
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Abstract

Organophosphorus pesticides (OPs) are a public health concern due to their worldwide use and documented human exposures. Phosphorothioate OPs are metabolized by cytochrome P450s (P450s) through either a dearylation reaction to form an inactive metabolite, or through a desulfuration reaction to form an active oxon metabolite, which is a potent cholinesterase inhibitor. This study investigated the rate of desulfuration (activation) and dearylation (detoxification) of methyl parathion and diazinon in human liver microsomes. In addition, recombinant human P450s were used to determine the P450-specific kinetic parameters (Km and Vmax) for each compound for future use in refining human physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of OP exposure. The primary enzymes involved in bioactivation of methyl parathion were CYP2B6 (Km = 1.25 μM; Vmax = 9.78 nmol · min−1 · nmol P450−1), CYP2C19 (Km = 1.03 μM; Vmax = 4.67 nmol · min−1 · nmol P450−1), and CYP1A2 (Km = 1.96 μM; Vmax = 5.14 nmol · min−1 · nmol P450−1), and the bioactivation of diazinon was mediated primarily by CYP1A1 (Km = 3.05 μM; Vmax = 2.35 nmol · min−1 · nmol P450−1), CYP2C19 (Km = 7.74 μM; Vmax = 4.14 nmol · min−1 · nmol P450−1), and CYP2B6 (Km = 14.83 μM; Vmax = 5.44 nmol · min−1 · nmol P450−1). P450-mediated detoxification of methyl parathion only occurred to a limited extent with CYP1A2 (Km = 16.8 μM; Vmax = 1.38 nmol · min−1 · nmol P450−1) and 3A4 (Km = 104 μM; Vmax = 5.15 nmol · min−1 · nmol P450−1), whereas the major enzyme involved in diazinon detoxification was CYP2C19 (Km = 5.04 μM; Vmax = 5.58 nmol · min−1 · nmol P450−1). The OP- and P450-specific kinetic values will be helpful for future use in refining human PBPK/PD models of OP exposure.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES016308-02S] through a Research Supplement to Promote Diversity in Health-Related Research (to C.A.E.); and the Environmental Protection Agency Science to Achieve Results [Grant R-83068301].

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

    http://dx.doi.org/10.1124/dmd.111.042572.

  • ABBREVIATIONS:

    OPs
    organophosphorus pesticides
    P450
    cytochrome P450
    PNP
    p-nitrophenol
    IMP
    pyrimidinol
    PBPK/PD
    physiologically based pharmacokinetic/pharmacodynamic
    Clint
    intrinsic clearance
    CAS
    Chemical Abstract Service
    iso-OMPA
    tetraisopropyl pyrophosphoramide
    HLM
    human liver microsomes
    HPLC
    high-performance liquid chromatography.

  • Received August 29, 2011.
  • Accepted October 3, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
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Rapid CommunicationShort Communication

P450-SPECIFIC METABOLISM OF METHYL PARATHION AND DIAZINON

Corie A. Ellison, Yuan Tian, James B. Knaak, Paul J. Kostyniak and James R. Olson
Drug Metabolism and Disposition January 1, 2012, 40 (1) 1-5; DOI: https://doi.org/10.1124/dmd.111.042572

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Rapid CommunicationShort Communication

P450-SPECIFIC METABOLISM OF METHYL PARATHION AND DIAZINON

Corie A. Ellison, Yuan Tian, James B. Knaak, Paul J. Kostyniak and James R. Olson
Drug Metabolism and Disposition January 1, 2012, 40 (1) 1-5; DOI: https://doi.org/10.1124/dmd.111.042572
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