Mitigation of Pennyroyal Oil Hepatotoxicity in the Mouse

Authors

  • Matthew D. Sztajnkrycer MD, PhD,

    Corresponding author
    1. Cincinnati Drug and Poison Information Center (MDS, EJO, GRB, RJG) University of Cincinnati, Cincinnati, OH (CJL)
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  • Edward J. Otten MD,

    1. Cincinnati Drug and Poison Information Center (MDS, EJO, GRB, RJG) University of Cincinnati, Cincinnati, OH (CJL)
    2. the Department of Emergency Medicine (MDS, EJO, RGB, CJL), University of Cincinnati, Cincinnati, OH (CJL)
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  • G. Randall Bond MD,

    1. Cincinnati Drug and Poison Information Center (MDS, EJO, GRB, RJG) University of Cincinnati, Cincinnati, OH (CJL)
    2. the Department of Emergency Medicine (MDS, EJO, RGB, CJL), University of Cincinnati, Cincinnati, OH (CJL)
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  • Christopher J. Lindsell PhD,

    1. the Department of Emergency Medicine (MDS, EJO, RGB, CJL), University of Cincinnati, Cincinnati, OH (CJL)
    2. Institute for Health Policy and Health Service Research, University of Cincinnati, Cincinnati, OH (CJL).
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  • Robert J. Goetz PharmD

    1. Cincinnati Drug and Poison Information Center (MDS, EJO, GRB, RJG) University of Cincinnati, Cincinnati, OH (CJL)
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Department of Emergency Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905. Fax: 507-255-6592; e-mail: sztajnkrycer.matthew@mayo.edu.

Abstract

Objectives: Pennyroyal oil ingestion has been associated with severe hepatotoxicity and death. The primary constituent, R-(+)-pulegone, is metabolized via hepatic cytochrome P450 to toxic intermediates. The purpose of this study was to assess the ability of the specific cytochrome P450 inhibitors disulfiram and cimetidine to mitigate hepatotoxicity in mice exposed to toxic levels of R-(+)-pulegone. Methods: 20-g female BALB/c mice were pretreated with either 150 mg/kg of cimetidine intraperitoneal (IP), 100 mg/kg of disulfiram IP, or both. After one hour, mice were administered 300 mg/kg of pulegone IP and were killed 24 hours later. Data were analyzed using ANOVA. Post-hoc t-tests used Bonferroni correction. Results: There was a tendency for lower serum glutamate pyruvate transaminase in the disulfiram and cimetidine groups compared with the R-(+)-pulegone group. The differences were significant for both the cimetidine and the combined disulfram and cimetidine groups compared with the R-(+)-pulegone group. Pretreatment with the combination of disulfiram and cimetidine most effectively mitigated R-(+)-pulegone–induced hepatotoxicity. Conclusions: Within the limitations of a pretreatment animal model, the combination of cimetidine and disulfiram significantly mitigates the effects of pennyroyal toxicity and does so more effectively than either agent alone. These data suggest that R-(+)-pulegone metabolism through CYP1A2 appears to be more important in the development of a hepatotoxic metabolite than does metabolism via CYP2E1.

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