Int. J. Environ. Res. Public Health 2010, 7 1083 mice and wild-type mice, even after chronic ethanol feeding [27]. These data show that the acceleration of alcohol metabolism caused by chronic ethanol feeing is not related to MEOS. We investigated the effects of chronic ethanol feeding on liver ADH isozymes under milder conditions than usual, using mice with about twice the rate of alcohol metabolism as that of rats and a liquid diet containing 4% ethanol, which corresponds to 28% of the total caloric intake [48]. After one week of feeding, the rate of alcohol metabolism increased as the total liver ADH activity increased, which was due to an increase in the liver ADH1 content. This situation continued until the 24th week of feeding, when a moderate case of fatty liver was observed. So, it seems that ADH1 adaptively contributes to the acceleration of alcohol metabolism induced by chronic ethanol feeing until the liver becomes moderately fatty, but that the contribution decreases as liver disease progresses, as observed in rats with a severe case of fatty liver. On the other hand, the liver ADH3 content markedly increased with the acute administration of a large dose (4.5 g/kg) of ethanol to mice during chronic ethanol feeding, although the liver ADH3 content did not significantly change when chronic ethanol feeding was mild [48]. This phenomenon may be related to acute alcoholic hepatitis or pancreatitis. It has been suggested that only ADH3 metabolizes ethanol in pancreatic acinar cells, which have almost the same ability to metabolize high concentrations of alcohol (50 mM) as hepatocytes do [49]. This also suggests that ADH3 is related to alcoholic pancreatic disease. 10. Induction of ADH3 Due to Cell Damage Accompanied by Increased Hydrophobicity ADH3 is strongly expressed in human atherosclerotic lesions of the coronary artery and in cultured rat smooth-muscle cells after lipofection, in both of which membrane damage and a hydrophobic state were observed [22]. These data suggest that ADH3 is induced by cell damage accompanied by increased hydrophobicity. So, the increase in liver ADH3 content observed in mice in the late stages of alcohol metabolism after the administration of a large dose of ethanol (Section 6) may be due to the cell damage and fatty change, which are observed in mouse liver late after a large dose of ethanol [50]. The marked increase in liver ADH3 content observed after the acute administration of a large dose of ethanol to chronic-ethanol-fed mice (Section 8) might have the same cause. Thus, the activity of ADH3 in the cells seems to be dynamically regulated by various intracellular conditions, for example, at the kinetic level, by solution hydrophobicity (Section 5), and at the enzyme content level, by hypoxia (Section 6) or by cell damage accompanied by increased hydrophobicity. ADH3 tends to be expressed especially strongly in cells in a critical condition because it plays a fundamental role in cell functions as the evolutionary ancestor of ADH, in contrast to ADH1, which differentiated from ADH3. The chronic intake of a large amount of alcohol forces to enhance ADH3 activity, but suppress ADH1 activity, through increased solution hydrophobicity and cell damage. Furthermore, ADH3 activity may be elevated throughout the body of alcoholics because it is ubiquitous. Thus, ADH 3 may play a greater role in the alcohol metabolism of alcoholics.