Increased toxicity of cocaine to human hepatocytes is observed when cells a
re simultaneously incubated with ethanol. Ethanol might exacerbate cocaine
hepatocyte toxicity by three different pathways: a) by increasing the oxida
tive metabolism of cocaine and hence the oxidative damage; b) by the format
ion of a more toxic metabolite, namely cocaethylene; or c) by decreasing th
e defence mechanisms of the cell (i.e. GSH). In the present study, experime
nts were conducted to investigate the feasibility of these hypotheses. In h
epatocytes preincubated for 48 hr with ethanol, neither significant changes
in cocaine metabolism nor cytotoxicity were found despite differences in h
epatocyte p-nitrophenol hydroxylase (largely CYP2E1 activity). Cocaethylene
, the transesterification product of cocaine and ethanol, was found to be m
ore toxic than cocaine for human hepatocytes (3x). However, the small amoun
t formed when human hepatocytes were incubated with cocaine and ethanol wou
ld hardly explain the increased toxicity observed. On the other hand, the s
imultaneous presence of cocaine and ethanol caused a sustained decline in t
he intracellular GSH content that was larger than that observed in cocaine-
or ethanol-treated cultures. Parallel to this phenomenon, a significant in
crease in lipid peroxidation was observed, as compared to cells treated wit
h equimolar amounts of cocaine, ethanol, or cocaethylene. Finally, depletio
n of hepatocyte GSH with diethylmaleate down to levels similar to those fou
nd in ethanol-treated cells made hepatocytes more susceptible to cocaine. T
aken together, the results of this research suggest that by decreasing GSH
levels, ethanol makes human hepatocytes more sensitive to cocaine-induced o
xidative damage. (C) 1999 Elsevier Science Inc.