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RESEARCH PRODUCT

Cocaine hepatotoxicity: two different toxicity mechanisms for phenobarbital-induced and non-induced rat hepatocytes.

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Abstract Hepatocytes isolated from both phenobarbital-induced and control rats were short-term cultured and exposed to cocaine (8–2000 μM) for varying times. Intracellular lactate dehydrogenase activity, free calcium levels ([Ca 2+ ] i ), reduced glutathione (GSH) and lipid peroxidation were investigated to evaluate the toxic effect of cocaine on hepatocytes. Cytochrome P450 induction by phenobarbital potentiated the in vitro cytotoxicity of cocaine by a factor of 13 (IC 50 = 84 μ M induced cells vs 1100 μM in non-induced cells). This difference in the susceptibility of the two types of hepatocytes to cocaine correlated well with the activity of cytochrome P450 2 B 1 2 . Rapid depletion of GSH, reaching 30% of the control levels, and massive lipid peroxidation thereafter were the two most remarkable phenomena preceding cell death in phenobarbital-induced hepatocytes. On the other hand, a sustained rise in [Ca 2+ ] i starting 2 hr after incubation with cocaine was the most noteworthy finding in non-induced liver cells. We suggest two different pathways for cocaine hepatotoxicity: in phenobarbital-induced hepatocytes oxidative metabolism of the drug causes GSH depletion, subsequent extensive lipid peroxidation and cell death, at low concentrations of cocaine. In non-induced hepatocytes these changes are less relevant, and the major alteration caused by cocaine is a non-transient rise in [Ca 2+ ] 1 that is evident at higher concentrations of the drug.