Alcohol use is common in the Americas and Western Europe and is increasing in the UK, Taiwan, Japan and Korea [24]. Chronic ethanol-induced hepatic disease is characterized by progressive evolution from steatosis to chronic hepatitis, fibrosis, cirrhosis and HCC [25]. How ever, HCC has been iden-tified in patients with alcohol-induced liver disease but without evident cirrhosis. Chron ic, heavy ethanol consumption was associated with a 5- to 7-fold increased risk for HCC development when ethanol use exceeded 80 g/day for more than 10 years. Habitual alcohol consumption acts synergistically with HBV infec tion: there is 3- to 4-fold elevated risk for development of HCC in patients with chronic HBV who habitually con sume alcohol. Relatively, there is an approximately 2-fold increased risk for HCC in patients with HCV and habitual alcohol consumption [24]. In both viral and alcohol medi ated liver damage, there is consistent evidence of enhanced production of free radicals and/or significant decrease of antioxidant defense. This leads to marked perturbation of the cellular redox status, with consequent oxidative stress [26].

Hepatocytes represent the major site of ethanol metabolism through three main pathways: alcohol dehydro genase [(ADH) located in the cytosol], the microsomal ethanol oxidizing system (MEOS), located in endoplasmic reticulum and comprised mainly of inducible cytochrome P450 2E1 (CYP2E1), and catalase (located in peroxi somes) [27]. The reactions of the ADH-dependent ethanol metabolism lead to production of reduced nicotinamide adenine dinucleotide (NADH), and results in increased oxygen use and in synthesis of reactive oxygen species (ROS) that cause peroxidation damage to DNA, lipids and proteins [1]. The intermediate acetaldehyde can cause additional ROS generation [1] and formation of DNA and protein adducts [1,28].

Microsomal CYP2E1 oxidizes carcinogens present in alcoholic beverages, tobacco smoke and the diet, thus enhancing their activation. The c2 allelic polymorphism of CYP2E1 gene is associated with increased CYP2E1 gene expression in patients with a history of alcohol use com pared with control HCC patients [24]. In addition, the induction of CYP2E1 can change immune system responses which leads to increased susceptibility to viral infections (e.g., HBV and HCV) [1]. Chronic alcohol abuse causes chronic immune system activation, which is the mechanism underlying alcohol-related liver disease [29]. Ethanol can cause several types of cell injury includ ing cell death. It is probably responsible for auto-activation of the normally quiescent zymogen proform of caspase-8, which further activates caspase-3, the final step in apoptotic cell death. It has been demonstrated that alco hol sensitizes primary hepatocytes and HepG2 cells to TNFá-mediated toxicity [25]. It also alters the activity of phospholipase C, phospholipase D, adenylate cyclase, PKC, JNK, p42/p44 MAPK, STAT and NFêB in hepatic tissues [27]. There is support for the possible role of etha nol in DNA methylation abnormalities in HCC via a decreased level of the hepatic methyladenosyltransferase II that results in decreased production of S-adenosyl methionine, the methyl donor for DNA methylation reactions[24].