Increased toxicity of cocaine on human hepatocytes induced by ethanol: Role of GSH

Citation
X. Ponsoda et al., Increased toxicity of cocaine on human hepatocytes induced by ethanol: Role of GSH, BIOCH PHARM, 58(10), 1999, pp. 1579-1585
Citations number
48
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
58
Issue
10
Year of publication
1999
Pages
1579 - 1585
Database
ISI
SICI code
0006-2952(19991115)58:10<1579:ITOCOH>2.0.ZU;2-Y
Abstract
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.