Induction of CYP2E1 by ethanol appears to be one of the main pathways by which ethanol can produce increased oxidative stress in the liver. The resulting oxidative stress can lead to enhanced lipid peroxidation and can also affect other important cellular components, such as protein or DNA. A reliable therapy for ethanol hepatotoxicity is presently not available. It appears possible that dietary and/or pharmacological agents capable of preventing ethanol-induced oxidative stress may reduce the incidence of ethanol toxicity in humans. New therapies may include inhibitors of CYP2E1, several which have been investigated experimentally, and polyenyl-phosphatidylcholine (PPC) which is particularly interesting because it is innocuous. Antioxidants such as silymarin, alpha-tocopherol and selenium are currently being tested. S-Adenosylmethionine (SAM) is also being studied as a protective agent since it can prevent some of the consequences of ethanol-induced oxidative stress in experimental animals and in humans. To study the biochemical and toxicological properties of CYP2E1-mediated oxidative stress, our laboratory established an in vitro cell culture model consisting of HepG2 cells overexpressing human CYP2E1 (E47 cells) incubated with either arachidonic acid (AA) or AA plus iron or BSO to deplete glutathione. All treatments resulted in cell toxicity, lipid peroxidation and mitochondrial membrane damage that could be prevented by inhibitors of CYP2E1 and antioxidants. Recent findings using this system have shown that spin trapping agents, such as Tempol and POBN, which act by scavenging various radical intermediates protect against arachidonic acid toxicity in E47 cells. Zinc pretreatment of E47 cells also protected against this toxicity probably through the induction of the antioxidant protein metallothionein. A manganese prophyrin complex protected E47 cells against AA plus iron toxicity acting as a scavenger of ROS. Adenovirus-mediated overexpression of catalase protected against AA plus iron as well as BSO toxicities in E47 cells. These various compounds protect against CYP2E1-induced oxidative stress and thus may have potential clinical utility for the prevention or improvement of ethanol-induced liver injury.