Int. J. Environ. Res. Public Health 2010, 7 1877 It has been proposed that ethanol metabolism causes proteasome inhibition [19] and that the initial molecular changes of ethanol injury are the reduction of both phosphorylation and activity of AMP-dependent protein kinase (AMPK). This contributes to the development of fatty liver by allowing increased activity of acetyl-CoA carboxylase [20,21]. Although alcoholic fatty liver resolves with alcohol abstinence, steatosis predisposes to the development of hepatic fibrosis and cirrhosis in people with continued pathological drinking patterns (Figure 1) [6]. Wu et al. mention that several mechanisms contribute to alcohol-induced liver injury, and that ethanol-induced oxidative stress is likely to arise from several sources, including CYP2E1, mitochondria, and activated Kupffer cells [17,22]. A central pathway appears to be the induction of cytochrome P450 2E1. It metabolizes and activates many toxicological substrates, including ethanol, to more reactive and toxic products [23]. This mechanism plays a role in creating a harmful condition known as oxidative stress, defined as the result of an imbalance between pro-oxidant and antioxidant systems [20]. This enhances the formation of free radicals which act in the lipidic wall membrane ongoing lipid peroxidation. ROS are intermediates in cell signaling pathways that alter gene expression and lead to cell proliferation, migration, and apoptosis; thus contribute to the development of chronic ethanol-induced liver injury [23]. When alcohol is consumed, CYP2E1 generates acetaldehyde as well as ROS in the cytosol of the cell, leading to an increase in oxidative stress with a probable mitochondrial origin. ROS are toxic to cells because they can react with most cellular macromolecules by inactivating enzymes or denaturing proteins, which causes DNA damage [6]. When alcohol is metabolized to acetaldehyde, the oxidized form NAD converts to the reduced form NADH. This reaction generates an excess of reduced equivalents which stimulates lipid biosynthesis [24]. Alcohol exposure increases nitrosative stress with elevated levels of ethanol-inducible CYP2E1, nitric oxide synthase, nitrite and mitochondrial hydrogen peroxide. Ethanol can also induce and/or activate inducible nitric oxid synthase (iNOS), which plays a key role in worsening alcohol-mediated hepatotoxicity. Moreover, the overexpression of CYP2E1 aggravates hepatic injury. Besides, expression of cytokeratins 8 and 18 can be considered as biomakers for ALD progression [25]. Alcohol intake also increases gut permeability, allowing bacterial endotoxins to enter the bloodstream and liver, where it can activate certain immune cells. Lipopolysaccharide (LPS) is an important activator of Kupffer cells requiring three cell proteins to complete the process: CD14, TLR4, and MD2. Activated Kupffer cells are responsible for an increased expression of TNFα and multiple inflammatory cytokines [26]. TNF-α is a mediator, not only in the early stages of fatty liver disease but also in the transition to more advanced stages of liver damage [27]. This activation is one of the earliest liver responses to injury. TNF-α is considered one of the most important cytokines involved in the pathogenesis of alcoholic liver bruise. Evidence indicates that disruption of the TNF-αR1 gene or treatment with a TNF-α neutralizing antibody, reduces alcoholic liver injury in mice. Alcohol-induced liver damage also depends on the host immune system susceptibility. Several studies have suggested that immune response plays a role in alcoholic liver disease. Pritchard et al. suggested the hypothesis that activation of the complement is required for the development of ethanol-induced fatty liver. They found that C3 contributed to accumulation of triglyceride in the liver,