Potentiation of cocaine-mediated hepatotoxicity by acute and chronic ethanol.
Cocaine has been associated with hepatotoxicities in man and is a potent hepatotoxin in mice. The theorized toxic metabolite of cocaine is thought to be generated by a multistep pathway mediated primarily by cytochrome P-450. Ethanol, whether administered acutely or chronically, is known to have diverse effects on numerous hepatocellular biochemical pathways. The present study was designed to characterize not only the effects of acute and chronic ethanol on cocaine-mediated hepatotoxicity but also on the hepatic reduced glutathione (GSH) in an attempt to correlate depletions of GSH with changes in toxicity. Male and female mice were administered an acute 50 mg/kg dose of cocaine either 1 hr after an acute 3 g/kg dose of ethanol, or after 5 days of consuming an ethanol-containing liquid diet. Serum alanine aminotransferase (ALT) activity was measured in blood collected 24 hr after the acute cocaine dose. In addition, hepatic reduced glutathione (GSH) and cytochrome P-450 content were measured at the point in the pretreatment where cocaine was administered. The results of this study indicate that both acute and chronic ethanol pretreatment can markedly enhance the hepatotoxicity of cocaine in both male and female mice and that the enhancement is significantly greater after chronic ethanol pretreatment. Hepatic GSH was slightly decreased 1 hr after an acute dose of ethanol and significantly decreased after chronic ethanol consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
Boyer
C S
CS
Molecular Toxicology and Environmental Health Sciences Program, School of Pharmacy, University of Colorado Health Sciences Center, Denver.
Petersen
D R
DR
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D003042:Cocaine / Q000633:toxicity*; D004357:Drug Synergism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D013997:Time Factors
D000431:Ethanol; D000410:Alanine Transaminase; D005978:Glutathione; D003042:Cocaine