Potentiation of cocaine hepatotoxicity by ethanol in human hepatocytes.
The hepatotoxic effects of cocaine on the human liver and the effect of ethanol on cocaine-induced hepatotoxicity have been examined in adult human hepatocytes cultured in chemically defined conditions. Cultures were exposed to concentrations of cocaine ranging from 10(-2) to 10(-5) M. Cytotoxicity was evaluated after 24 hr of continuous exposure to cocaine by measuring the leakage of intracellular LDH and the ability of cells to reduce MTT. According to these end-point parameters, half-maximal cytotoxic concentrations of cocaine for human hepatocytes (IC50) were 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 for 24 hr 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. For most of the metabolic parameters assayed, significant alterations were observed at 0.5 mM cocaine. Glycogen reloading of hepatocytes began to be inhibited in the presence of 0.60 mM cocaine (IC10). Ethanol greatly potentiated cocaine-induced hepatotoxicity. After a 48 hr pretreatment of human hepatocytes with 50 mM ethanol, low concentration 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% degradation of glycogen stores, and a 30% reduction in glutathione content. The results of our work show that ethanol increases the effects of cocaine on human hepatocytes by a factor of 10.
Jover
R
R
Unidad de Hepatología Experimental, Centro de Investigación, Valencia, Spain.
Ponsoda
X
X
Gómez-Lechón
M J
MJ
Herrero
C
C
del Pino
J
J
Castell
J V
JV
D002478:Cells, Cultured; D003042:Cocaine / Q000633:toxicity*; D004357:Drug Synergism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged
D000431:Ethanol; D003042:Cocaine