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Biotransformation of parathion in human liver: participation of CYP3A4 and its inactivation during microsomal parathion oxidation.

Abstract

Studies in rat liver have shown that cytochrome P450 (CYP) enzymes mediate the oxidative biotransformation of the phosphorothioate pesticide parathion to paraoxon and 4-nitrophenol. Transfer of the phosphorothioate thionosulfur atom to the CYP apoprotein results in amino acid modification and enzyme inactivation. Our study investigated the role of human hepatic CYP in parathion oxidation and their relative susceptibilities to inhibition and inactivation. Rates of parathion oxidation varied about 10-fold in microsomes from 23 individual livers (1.72-18.33 nmol total metabolites/mg protein/min). Linear regression of rates of parathion oxidation with those of other microsomal CYP reactions implicated CYP3A4 in the reaction. Thus, parathion oxidation was correlated strongly with testosterone 6beta-hydroxylation (r2 = 0.95, n = 11), but not with activities mediated by CYP 1A2, 2C9 or 2E1. CYP 3A4 expressed in lymphoblastoid cell lines was an efficient catalyst of parathion oxidation, although CYP 1A2 and 2B6 also catalyzed the activity. The CYP3A4 inhibitors ketoconazole and triacetyloleandomycin decreased the observed rate of microsomal parathion oxidation, but chemicals known to interact preferentially with other human CYP were essentially noninhibitory. P450 was lost during parathion biotransformation in human hepatic microsomes. Thus, incubation (10 min) of parathion (25 microM) with NADPH-supplemented microsomes led to an apparent 19 +/- 4% decrease in holo-P450 content. Several CYP-specific oxidation reactions were inhibited and inactivated by parathion. Testosterone 6beta-hydroxylation (mediated by CYP3A4), 7-ethylresorufin O-deethylation (CYP1A2) and tolbutamide methyl hydroxylation (CYP2C9/10), but not aniline 4-hydroxylation (CYP2E1), were inhibited effectively by parathion. Preincubation of microsomes with parathion and NADPH intensified the extent of inhibition (i.e., elicited inactivation) of reactions mediated by 3A4 and 1A2 and, to a lesser extent, 2C9. In summary, these findings strongly implicate CYP 3A4 as the principal catalyst of parathion oxidation in human liver, although other CYP may play a lesser role. During parathion oxidation CYP3A4 undergoes significant inactivation. In view of the role of this enzyme in the oxidation of many therapeutic agents, exposure to phosphorothioate pesticides may adversely affect drug elimination in humans.

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  • Authors+Show Affiliations

    ,

    Department of Medicine, University of Sydney, Westmead Hospital, Australia.

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    MeSH

    Aniline Hydroxylase
    Animals
    Aryl Hydrocarbon Hydroxylases
    Biotransformation
    Cell Line
    Cytochrome P-450 CYP1A1
    Cytochrome P-450 CYP1A2
    Cytochrome P-450 CYP2C9
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme Inhibitors
    Cytochrome P-450 Enzyme System
    Cytochromes
    Enzyme Inhibitors
    Humans
    Kinetics
    Liver
    Microsomes, Liver
    Mixed Function Oxygenases
    Oxidation-Reduction
    Parathion
    Rats
    Regression Analysis
    Steroid 16-alpha-Hydroxylase
    Steroid Hydroxylases
    Substrate Specificity

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    9023313

    Citation

    Butler, A M., and M Murray. "Biotransformation of Parathion in Human Liver: Participation of CYP3A4 and Its Inactivation During Microsomal Parathion Oxidation." The Journal of Pharmacology and Experimental Therapeutics, vol. 280, no. 2, 1997, pp. 966-73.
    Butler AM, Murray M. Biotransformation of parathion in human liver: participation of CYP3A4 and its inactivation during microsomal parathion oxidation. J Pharmacol Exp Ther. 1997;280(2):966-73.
    Butler, A. M., & Murray, M. (1997). Biotransformation of parathion in human liver: participation of CYP3A4 and its inactivation during microsomal parathion oxidation. The Journal of Pharmacology and Experimental Therapeutics, 280(2), pp. 966-73.
    Butler AM, Murray M. Biotransformation of Parathion in Human Liver: Participation of CYP3A4 and Its Inactivation During Microsomal Parathion Oxidation. J Pharmacol Exp Ther. 1997;280(2):966-73. PubMed PMID: 9023313.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Biotransformation of parathion in human liver: participation of CYP3A4 and its inactivation during microsomal parathion oxidation. AU - Butler,A M, AU - Murray,M, PY - 1997/2/1/pubmed PY - 1997/2/1/medline PY - 1997/2/1/entrez SP - 966 EP - 73 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 280 IS - 2 N2 - Studies in rat liver have shown that cytochrome P450 (CYP) enzymes mediate the oxidative biotransformation of the phosphorothioate pesticide parathion to paraoxon and 4-nitrophenol. Transfer of the phosphorothioate thionosulfur atom to the CYP apoprotein results in amino acid modification and enzyme inactivation. Our study investigated the role of human hepatic CYP in parathion oxidation and their relative susceptibilities to inhibition and inactivation. Rates of parathion oxidation varied about 10-fold in microsomes from 23 individual livers (1.72-18.33 nmol total metabolites/mg protein/min). Linear regression of rates of parathion oxidation with those of other microsomal CYP reactions implicated CYP3A4 in the reaction. Thus, parathion oxidation was correlated strongly with testosterone 6beta-hydroxylation (r2 = 0.95, n = 11), but not with activities mediated by CYP 1A2, 2C9 or 2E1. CYP 3A4 expressed in lymphoblastoid cell lines was an efficient catalyst of parathion oxidation, although CYP 1A2 and 2B6 also catalyzed the activity. The CYP3A4 inhibitors ketoconazole and triacetyloleandomycin decreased the observed rate of microsomal parathion oxidation, but chemicals known to interact preferentially with other human CYP were essentially noninhibitory. P450 was lost during parathion biotransformation in human hepatic microsomes. Thus, incubation (10 min) of parathion (25 microM) with NADPH-supplemented microsomes led to an apparent 19 +/- 4% decrease in holo-P450 content. Several CYP-specific oxidation reactions were inhibited and inactivated by parathion. Testosterone 6beta-hydroxylation (mediated by CYP3A4), 7-ethylresorufin O-deethylation (CYP1A2) and tolbutamide methyl hydroxylation (CYP2C9/10), but not aniline 4-hydroxylation (CYP2E1), were inhibited effectively by parathion. Preincubation of microsomes with parathion and NADPH intensified the extent of inhibition (i.e., elicited inactivation) of reactions mediated by 3A4 and 1A2 and, to a lesser extent, 2C9. In summary, these findings strongly implicate CYP 3A4 as the principal catalyst of parathion oxidation in human liver, although other CYP may play a lesser role. During parathion oxidation CYP3A4 undergoes significant inactivation. In view of the role of this enzyme in the oxidation of many therapeutic agents, exposure to phosphorothioate pesticides may adversely affect drug elimination in humans. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9023313/Biotransformation_of_parathion_in_human_liver:_participation_of_CYP3A4_and_its_inactivation_during_microsomal_parathion_oxidation_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9023313 DB - PRIME DP - Unbound Medicine ER -