RT Journal Article
SR Electronic
T1 Liver Toxicity from Norcocaine Nitroxide, an N-Oxidative Metabolite of Cocaine
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 413
OP 419
VO 284
IS 1
A1 Florence M. Ndikum-Moffor
A1 Trenton R. Schoeb
A1 Stephen M. Roberts
YR 1998
UL http://jpet.aspetjournals.org/content/284/1/413.abstract
AB The oxidative metabolism of cocaine to norcocaine nitroxide has been postulated to be essential for cocaine hepatotoxicity. The hepatic effects of norcocaine nitroxide have never been evaluated in vivo, however. In this study mice were administered norcocaine nitroxide i.p., and hepatotoxicity was assessed using serum alanine aminotransferase activities and microscopic examination of liver tissue. Hepatotoxicity of norcocaine nitroxide was dose-related; significant injury was detectable at doses of 20 to 30 mg/kg i.p., and severe hepatocellular necrosis was observed at doses of 40 and 50 mg/kg. Elevated serum alanine aminotransferase activities peaked between 12 and 18 hr after norcocaine nitroxide treatment. Electron microscopy revealed the presence of pronounced changes in cell morphology as early as 30 min after the norcocaine nitroxide dose. Pretreatment of mice with phenobarbital had no effect on the magnitude of hepatic injury but shifted the intralobular site of necrosis from the midzonal to the periportal region. Pretreatment with diazinon, an esterase inhibitor, increased norcocaine nitroxide-induced liver damage, whereas each of the P450 inhibitors SKF 525A, cimetidine, troleandomycin, ketaconazole and chloramphenicol significantly diminished norcocaine nitroxide hepatotoxicity. The results indicate that norcocaine nitroxide is hepatotoxic and suggest the involvement of P450 enzymes. The American Society for Pharmacology and Experimental Therapeutics