Int. J. Environ. Res. Public Health 2010, 7 1077 total liver ADH activity to both ADH1 and ADH3 explains the dose-dependent changes in the pharmacokinetic parameters (, CLT, AUC) of blood ethanol very well, suggesting that alcohol metabolism in mice is primarily governed by these two ADHs. In patients with alcoholic liver disease, liver ADH3 activity increases, while ADH1 activity decreases, as alcohol intake increases. Furthermore, ADH3 is induced in damaged cells that have greater hydrophobicity, whereas ADH1 activity is lower when there is severe liver disease. These data suggest that chronic binge drinking and the resulting liver disease shifts the key enzyme in alcohol metabolism from low-Km ADH1 to high-Km ADH3, thereby reducing the rate of alcohol metabolism. The interdependent increase in the ADH3/ADH1 activity ratio and AUC may be a factor in the development of alcoholic liver disease. However, the adaptive increase in ADH3 sustains alcohol metabolism, even in patients with alcoholic liver cirrhosis, which makes it possible for them to drink themselves to death. Thus, the regulation of ADH3 activity may be important in preventing alcoholism development. Keywords: ADH1; ADH3; contribution to alcohol metabolism; enzyme regulation; role shift; alcoholic liver disease 1. Introduction The pharmacologic and potentially pathologic effects of alcohol depend on the concentrations of ethanol and its metabolites in the body, and on the duration of exposure to these substances. When the body ingests ethanol, there is an initial equilibration phase, after which both the concentrations and duration of these substances in the body are primarily governed by the rate of ethanol metabolism. So, the elucidation of the mechanism of alcohol metabolism is essential to the understanding and control of the action of alcohol in the body. Alcohol dehydrogenase (ADH) 1 (Class I ADH) is the key enzyme in alcohol metabolism in vivo [1]. However, it has been demonstrated that systemic alcohol metabolism involves another pathway independent of ADH1 [2,3]. This was originally called the non-ADH1 pathway, and is thought to play a major role in alcohol metabolism for acute intoxication and for chronic drinkers [2-7]. Thus, the identification of the enzyme in this pathway has long been the subject of heated scientific debate, with the main candidates being the microsomal ethanol oxidizing system (MEOS) and catalase [2-12]. However, the contributions of these two enzymes to systemic alcohol metabolism have still not been clarified. In 1978, we found a new type of ADH in mouse liver [13,14], which was later classified as Class III ADH (ADH3) [14,15], and have continued to investigate its enzymatic characteristics and its role in alcohol metabolism [16-24]. Recently, we used ADH3-null mutant mice to demonstrate that the contribution of ADH3 to alcohol metabolism in vivo increases dose-dependently [25]. In this review, we argue for a new view of ADH3 in alcohol metabolism and in the development of alcoholism, and compare it with ADH1, which has the starring role in the field of alcohol medicine.