COCAINE HEPATOTOXICITY - 2 DIFFERENT TOXICITY MECHANISMS FOR PHENOBARBITAL-INDUCED AND NONINDUCED RAT HEPATOCYTES

Hepatocytes isolated from both phenobarbital-induced and control rats were short-term cultured and exposed to cocaine (8-2000 mu M) for vary ing times. Intracellular lactate dehydrogenase activity, free calcium levels ([Ca2+](i)), reduced glutathione (GSH) and lipid peroxidation w ere investigated to evaluate the toxic effect of cocaine on hepatocyte s. Cytochrome P450 induction by phenobarbital potentiated the in vitro cytotoxicity of cocaine by a factor of 13 (IC50 = 84 mu M in induced cells vs 1100 mu M in non-induced cells). This difference in the susce ptibility of the two types of hepatocytes to cocaine correlated well w ith the activity of cytochrome P450 2B1/2. Rapid depletion of GSH, rea ching 30% of the control levels, and massive lipid peroxidation therea fter were the two most remarkable phenomena preceding cell death in ph enobarbital-induced hepatocytes. On the other hand, a sustained rise i n [Ca2+](i) starting 2 hr after incubation with cocaine was the most n oteworthy finding in non-induced liver cells. We suggest two different pathways for cocaine hepatotoxicity: in phenobarbital-induced hepatoc ytes 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+](i) that is evident at higher concentrations of the drug.