Int. J. Environ. Res. Public Health 2010, 7 1084 11. Role of ADH3 in Liver Disease and the Alcohol Metabolism of Alcoholics When hexenol is used as a substrate in an ADH assay, 4-methlypyrazole has no effect on ADH3 activity, but it completely inhibits ADH1 activity [43]. So, we used hexenol and 4-methlypyrazole to measure the liver ADH1 and ADH3 activities of alcoholics with liver disease [18]. The total ADH and ADH1 activities of biopsied livers correlate directly with each other and inversely with the amount of alcohol intake per day. These activities are relatively high in normal livers and in livers with mild fibrosis, but are low in fatty livers and very low in livers with severe fibrosis and cirrhosis. Taking these results together with those for chronically-ethanol-fed mice (Section 8), we conclude that chronic drinking adaptively increases ADH1 activity to accelerate alcohol metabolism until the onset of mild liver disease. However, a further increase in alcohol intake reduces ADH1 activity and its role in alcohol metabolism due to the development of liver disease. On the other hand, ADH3 activity significantly correlates with a person’s total alcohol intake, which strongly correlates with the development of liver disease. Consequently, ADH3 activity inversely correlates with ADH1 activity in alcoholic patients. This relationship can be also explained by the idea that ADH 3 is induced by cell damage accompanied by increased hydrophobicity. In addition, capillarization of the liver due to liver cirrhosis may also increase the amount of ADH3, because it is mainly found in the sinusoidal endothelial cells of the liver [19]. The highest incidence of liver cirrhosis is observed in patients with a high ADH3/ADH1 activity ratio plus low total liver ADH activity. As discussed in the complex two-ADH model for mice, the key enzyme in alcohol metabolism may also shift from ADH1 to ADH3 in alcoholic patients with severe liver disease. For these patients, liver disease may have developed through a nonlinear increase in AUC due to an increase in the ADH3/ADH1 activity ratio that accompanies the lower rate of alcohol metabolism. Cases are not rare in which alcoholics with liver cirrhosis visit a hospital after drinking a great deal of alcohol the day before. How can they drink so much even though ADH1, MEOS [51], and catalase [52], which are well-known alcohol-oxidizing enzymes, all have a low activity in their livers? It is difficult to explain the alcohol metabolism of such patients solely in terms of these enzymes. On the other hand, ADH3 is induced by cell damage that produces hydrophobicity [22] and positively correlates with lifetime total alcohol intake [18], which is strongly related to the development of liver disease. So, this ADH may maintain the ability of alcoholic patients to metabolize alcohol in spite of severe liver disease, thereby making it possible for them to drink a great deal. In summary, the development of alcoholism is adequately described by a complex two-ADH model. Chronic drinking accelerates alcohol metabolism by means of an adaptive increase in ADH1 activity (and also ADH3 activity under some conditions) during the non-pathological stage. Induced alcohol resistance increases the amount of alcohol that can be imbibed, and leads to heavy drinking. The increased AUC from heavy drinking elevates the cellular toxicity and central-nervous-system toxicity of alcohol. Cell damage accompanied by hydrophobicity reduces the rate of alcohol metabolism through an increase in the ADH3/ADH1 activity ratio, which in turn produces a further nonlinear increase in AUC. The vicious cycle of an interdependent increase in the ADH3/ADH1 activity ratio and AUC in alcohol dependence may further develop liver disease and induce cirrhosis of the liver. However, this adaptation of ADH3 to alcohol metabolism may mean suicide to alcoholics, because it makes it possible for them to keep on drinking by maintaining the ability to metabolize alcohol even