Ethanol does not increase the hepatotoxicity of cocaine in primary rat hepatocyte culture.
Rat hepatocytes were utilized to investigate the role of cocaine metabolism and the contribution of ethylcocaine formation to cocaine-induced liver damage. Hepatocytes were prepared from rats pretreated with saline, phenobarbital or ethanol and exposed to cocaine, ethanol, or their combination. Hepatotoxicity was assessed by lactate dehydrogenase (LDH) leakage and was correlated with cocaine metabolism which was assessed quantitatively using HPLC. Only phenobarbital-pretreatment produced increases in LDH leakage from cultures exposed to cocaine. This increase in LDH release occurred simultaneous to a decrease in benzoylecognine formation and a marked increase in norcocaine generation. Exposing cultures to ethanol alone did not result in LDH leakage from hepatocytes. Furthermore, including ethanol in cultures treated with cocaine did not enhance the LDH leakage produced by cocaine alone. This study confirms quantitatively that cocaine-induced hepatotoxicity is mediated through cocaine oxidative events and is enhanced by microsomal induction produced by phenobarbital. The finding that ethylcocaine formation was maximal in the ethanol-pretreatment group where no toxicity was observed suggests that ethylcocaine is not the agent responsible for the hepatotoxicity observed in this study.
Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, Graduate School of Biomedical Sciences, Newark 07103-2714, USA.
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Abdel-Rahman
D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity*; D004357:Drug Synergism; D000431:Ethanol / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000431:Ethanol; D007770:L-Lactate Dehydrogenase; C066444:cocaethylene; D003042:Cocaine; D010634:Phenobarbital