Potentiation of cocaine hepatotoxicity in human hepatocytes by ethanol.
The cytotoxic effect of cocaine on human hepatocytes was evaluated after 24 hr of exposure to cocaine by measuring the leakage of intracellular lactate dehydrogenase and the reduction of MTT. According to these endpoint parameters, the half-maximal cytotoxic concentration (IC(50)) of cocaine was 6.8 and 7.8 mm, respectively. Lower concentrations of cocaine, however, impaired basic metabolic functions of human hepatocytes. Exposure of cells to 2 mm-cocaine resulted in a 50% decrease in hepatic glycogen, a 40% decrease in cellular glutathione content and a 40% decrease in urea synthesis with respect to control values. Ethanol greatly potentiated cocaine-induced hepatotoxicity. After a 48-hr pretreatment of human hepatocytes with 50 mm-ethanol, concentrations of cocaine (0.25 mm) that had no effects on hepatocyte metabolism in the absence of ethanol, caused a 20% inhibition of the urea synthesis rate, a 40% depletion of glycogen stores and a 30% reduction in glutathione content. The results of our work show that ethanol significantly increases the toxic effects of cocaine on human hepatocytes.
Ponsoda
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Unidad de Hepatología Experimental, Centro de Investigación, Hospital Universitario "La Fe", SVS. Avda. Campanar 21, E-46009 Valencia, Spain.
Jover
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R
Castell
J V
JV
Gómez-Lechón
M J
MJ