Increased toxicity of cocaine on human hepatocytes induced by ethanol: role of GSH.
Increased toxicity of cocaine to human hepatocytes is observed when cells are simultaneously incubated with ethanol. Ethanol might exacerbate cocaine hepatocyte toxicity by three different pathways: a) by increasing the oxidative metabolism of cocaine and hence the oxidative damage; b) by the formation of a more toxic metabolite, namely cocaethylene; or c) by decreasing the defence mechanisms of the cell (i.e. GSH). In the present study, experiments were conducted to investigate the feasibility of these hypotheses. In hepatocytes preincubated for 48 hr with ethanol, neither significant changes in cocaine metabolism nor cytotoxicity were found despite differences in hepatocyte p-nitrophenol hydroxylase (largely CYP2E1 activity). Cocaethylene, the transesterification product of cocaine and ethanol, was found to be more toxic than cocaine for human hepatocytes (3x). However, the small amount formed when human hepatocytes were incubated with cocaine and ethanol would hardly explain the increased toxicity observed. On the other hand, the simultaneous presence of cocaine and ethanol caused a sustained decline in the intracellular GSH content that was larger than that observed in cocaine- or ethanol-treated cultures. Parallel to this phenomenon, a significant increase in lipid peroxidation was observed, as compared to cells treated with equimolar amounts of cocaine, ethanol, or cocaethylene. Finally, depletion of hepatocyte GSH with diethylmaleate down to levels similar to those found in ethanol-treated cells made hepatocytes more susceptible to cocaine. Taken together, the results of this research suggest that by decreasing GSH levels, ethanol makes human hepatocytes more sensitive to cocaine-induced oxidative damage.
Ponsoda
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Unidad de Hepatología Experimental, Centro de Investigación, Hospital La Fe, Valencia, Spain.
Bort
R
R
Jover
R
R
Gómez-Lechón
M J
MJ
Castell
J V
JV
D000368:Aged; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress
D018765:Dopamine Uptake Inhibitors; D000431:Ethanol; D005982:Glutathione Transferase; C066444:cocaethylene; D003042:Cocaine