Mitigation of pennyroyal oil hepatotoxicity in the mouse.
OBJECTIVE
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.
Sztajnkrycer
Matthew D
MD
Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, USA. sztajnkrycer.matthew@mayo.edu
Otten
Edward J
EJ
Bond
G Randall
GR
Lindsell
Christopher J
CJ
Goetz
Robert J
RJ
D000818:Animals; D016022:Case-Control Studies; D002927:Cimetidine / Q000627:therapeutic use*; D000081005:Cyclohexane Monoterpenes; D003512:Cyclohexanones / Q000506:poisoning*; D004195:Disease Models, Animal; D004221:Disulfiram / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D031336:Hedeoma; D008107:Liver Diseases / Q000209:etiology / Q000517:prevention & control*; D031335:Mentha pulegium; D051379:Mice; D008807:Mice, Inbred BALB C; D039821:Monoterpenes / Q000506:poisoning*; D009822:Oils, Volatile / Q000506:poisoning*
D000081005:Cyclohexane Monoterpenes; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D039821:Monoterpenes; D009822:Oils, Volatile; C039648:pulegone; D002927:Cimetidine; C022156:pennyroyal oil; D004221:Disulfiram