Int. J. Environ. Res. Public Health 2010, 7 1086 a wide specificity for substrates and is responsible for various metabolic functions essential for life, including the detoxification of cytotoxins. So, it is easy to imagine that, in heavy drinkers, the continuous drinking of alcohol disturbs the basic metabolism and causes the collapse of homeostasis by inhibiting the many functions of ADH3. The idea that alcohol-related disorders are induced when ethanol inhibits physiological metabolism through the mechanism of ADHs is as important as ideas on the toxicity of ethanol and its metabolites themselves. 14. Conclusion This review described a new view of ADH 3 in the fields of alcohol metabolism and the bioaction of ethanol, and compared the new face of ADH3 to the well-known ADH1. ADH 3 contributes to alcohol metabolism during acute alcohol intoxication and diminishes the symptoms, thereby supporting ADH1. Solution hydrophobicity increases ADH3 activity at the kinetic level, and cell damage accompanied by hydrophobicity does so at the enzyme content level. A dose of alcohol large enough to damage the liver increases the ADH3/ADH1 activity ratio and lowers the rate of alcohol metabolism, which in turn nonlinearly increases the AUC. The interdependent increase in AUC and the ADH3/ADH1 activity ratio may be a factor in the development of liver disease. In alcoholics with liver disease, ADH3 activity increases with total alcohol intake, while ADH1 activity decreases. This suggests that ADH3 plays an important role in the alcohol metabolism of alcoholics with severe liver disease, compensating for the reduced role of ADH1. This adaptive role of ADH3 after chronic binge drinking makes it possible for alcoholics to drink themselves to death in spite that the rate of alcohol metabolism is lowered. Thus, it may be important to regulate ADH3 activity to prevent the development of alcoholism. Our theory about alcohol metabolism and alcoholism is still at the research level. We welcome a thorough examination of it through experiments and discussions in various fields. Acknowledgments We would like to thank all colleagues who have collaborated with us or supported us and made suggestions about this study. This work was financially supported in part by a grant-in-aid from the Ministry of Education, Science and Culture, Japan from the Japan Society for the Promotion of Science and from the Promotion and Mutual Cooperation for Private Schools of Japan. References and Notes 1. Crow, K.E.; Hardman, M.J. Regulation of rates of ethanol metabolism. In Regulation, Enzymology, and Metabolites of Ethanol, Human Metabolism of Alcohol; Crow, K.E., Batt, R.D., Eds.; CRC Press Inc.: Boca Raton, FL, USA, 1989; Volume 2, pp. 3-16. 2. Lieber, C.S.; DeCarli, L.M. The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo. J. Pharmacol. Exp. Ther. 1972, 181, 279-287.