The mechanisms by which alcohol causes cell injury are not clear. A major mechanism that is the focus of considerable research is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a role in how alcohol induces oxidative stress. Considerable attention has been given to alcohol-elevated production of lipopolysaccharide (LPS) and TNFa and to alcohol induction of CYP2E1. These two pathways are not exclusive of each other, however, associations and interactions between them, especially in vivo, have not been extensively evaluated. We have shown that increased oxidative stress from induction of CYP2E1 in vivo sensitizes hepatocytes to LPS and TNF toxicity and that oxidants, such as peroxynitrite, activation of p38 and JNK MAP kinases, inactivation of NF-kB protective pathways and mitochondrial dysfunction are downstream mediators of this CYP2E1-LPS/TNF potentiated hepatotoxicity. This review will summarize studies showing potentiated interactions between these two risk factors in promoting liver injury and the mechanisms involved.Keywords Alcohol Á CYP2E1 Á Lipopolysaccharide Á Oxidative stress Á Tumor necrosis factor alpha Alcohol, oxidative stress and cell injuryThe ability of acute and chronic ethanol treatment to increase production of reactive oxygen species and to enhance peroxidation of lipids, protein, and DNA has been demonstrated in a variety of systems, cells, and species, including humans [3]. Despite a tremendous growth in understanding alcohol metabolism and actions, the mechanism(s) by which alcohol causes cell injury are still not clear. A variety of leading mechanisms has been briefly summarized [13,17,67], and it is likely that many of them ultimately converge as they reflect a spectrum of the organism's response to the myriad of direct and indirect actions of alcohol. A major mechanism that is a focus of considerable research is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a key role in how ethanol induces ''oxidative stress''. Some of these include redox state changes (decrease in the NAD ? /NADH redox ratio) produced as a result of ethanol oxidation by alcohol and aldehyde dehydrogenases; production of the reactive product acetaldehyde as a consequence of ethanol oxidation by all major oxidative pathways; damage to mitochondria which results in decreased ATP production; direct or membrane effects caused by hydrophobic ethanol interaction with either phospholipids or protein components or enzymes; ethanol-induced hypoxia, especially in the pericentral zone of the liver acinus as oxygen is consumed in order for the liver to detoxify ethanol via oxidation; ethanol effects on the immune system, and altered cytokine production; ethanol-induced increase in bacterialderived endotoxin with subsequent activation of Kupffer cells; ethanol induction of CYP2E1; ethanol mobilization of iron which results in enhanced levels of low molecular weight non-heme iron; effects...