The effects of phencyclidine pretreatment on cocaine-mediated hepatotoxicity in mice

Toxicology and Applied Pharmacology
M J Reid, L M Bornheim

Abstract

Cocaine-mediated hepatotoxicity (CMH) requires cocaine (CCN) bioactivation by microsomal monooxygenase enzymes that results in cell death. Proposed mechanisms of toxicity involve reactive metabolites that covalently bind to hepatocellular proteins, depletion of cellular reducing equivalents through redox cycling, and/or the generation of reactive oxygen and nitrogen species that alter lipids and proteins. We have previously shown that phencyclidine (PCP) pretreatment potentiated CMH in CF-1 mice without increasing in vitro N-demethylation or N-hydroxylation of CCN. We have now further characterized PCP-potentiated CMH and determined that it is a dose- and time-dependent process, with PCP doses as low as 2.5 mg/kg for 3 days significantly increasing CMH. Immunohistochemistry and histology of livers from mice pretreated with PCP before CCN administration revealed a marked correlation between the regions of CCN metabolite binding and that of necrosis, whereas there was little binding or necrosis in vehicle-pretreated mice. Although hepatic GSH levels were not altered after repetitive PCP treatment alone, a sustained decrease (at least 6 h) in these levels was observed following CCN administration. Inhibitors of inducible nitric ox...Continue Reading

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Citations

Jul 23, 2002·Journal of Toxicology and Environmental Health. Part a·Ramez LabibMohamed S Abdel-Rahman
Aug 23, 2003·International Journal of Toxicology·Ramez LabibMohamed S Abdel-Rahman
Oct 13, 2006·Current Opinion in Gastroenterology·James H Lewis

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