Elsevier

Biochemical Pharmacology

Volume 46, Issue 11, 3 December 1993, Pages 1967-1974
Biochemical Pharmacology

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

https://doi.org/10.1016/0006-2952(93)90638-DGet rights and content

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 ([Ca2+]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 (IC50 = 84 μM 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 2B12. 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 [Ca2+]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 [Ca2+]1 that is evident at higher concentrations of the drug.

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