Potentiation of heroin and methadone hepatotoxicity by ethanol: an in vitro study using cultured human hepatocytes.
1. The hepatotoxic effects of heroin and methadone, and the effect of ethanol on opioid-induced hepatotoxicity, have been investigated in human cultured hepatocytes. Hepatocytes pretreated with 50 and 100 mM ethanol were exposed to increasing concentrations of heroin and methadone. 2. Cytotoxicity was evaluated by measuring leakage of intracellular lactate dehydrogenase, and by assessment of hepatocyte mitochondrial succinate dehydrogenase. The half-maximal cytotoxic concentration of heroin for human hepatocytes (TC50) was decreased by 70-55% by pre-exposure to 50 mM ethanol, and that for methadone was decreased by 60-40%. 3. Metabolic functions of human hepatocytes were significantly impaired at concentrations of opioids that had shown little cytotoxicity. Ethanol potentiated opioid-induced hepatotoxicity; concentrations of heroin and methadone that had little or no effect on hepatocyte metabolism in the absence of ethanol caused a significant decrease in urea synthesis rate, metabolism of glycogen and depletion of the intracellular GSH pool after ethanol pretreatment. 4. The increase in toxicity of heroin and methadone produced by ethanol is concomitant with a 40% increase in cytochrome P-450 levels of the pretreated hepatocytes.
Jover
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Unidad de Hepatología Experimental, Centro de Investigación, Hospital La Fe, Valencia, Spain.
Ponsoda
X
X
Gómez-Lechón
M J
MJ
Castell
J V
JV
D001706:Biopsy; D002478:Cells, Cultured; D004347:Drug Interactions; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D003932:Heroin / Q000633:toxicity*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008691:Methadone / Q000633:toxicity*; D010084:Oxidation-Reduction; D011446:Prospective Studies; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014508:Urea / Q000378:metabolism
D013778:Tetrazolium Salts; D013844:Thiazoles; D000431:Ethanol; D003932:Heroin; D014508:Urea; D006003:Glycogen; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue; D005978:Glutathione; D008691:Methadone