Int. J. Environ. Res. Public Health 2010, 7 1085 when there is severe liver disease, which could be fatal. This seems to be an adaptive discrepancy in human physiology. From another standpoint, however, the regulation of ADH3 activity seems to be a key to resolving the problem of alcoholism. 12. Other ADH Isozymes in Alcohol Metabolism ADH2 (Class II), which shows limited distribution to the liver [53], seems to be insignificant in alcohol metabolism of rodents, because mouse ADH2 is responsible for only a small part of the total ADH activity in the liver (Section 3). On the other hand, human ADH2 is known to be highly active towards ethanol [54], and is suggested to contribute to alcohol metabolism [55,56]. However, its contribution possibility to systemic alcohol metabolism may become lower in habitual drinking, because ADH2 activity has been demonstrated to be decreased in baboon liver by moderate drinking and to be almost abolished by heavy drinking [57]. ADH4 (Class IV) also shows restricted distribution to gastric mucosa, exhibiting different kinetics for ethanol between human (Km = ~37 mM) and rodents (Km = ~2.4 M) [58]. The catalytic efficiency is about 40-times higher in human than in rodent. However, the tissue content of human ADH4 in gastric mucosa is approximately 10 μg/g tissue [58], which is less than 1/40 of the contents of ADH1 or 3 in the liver [20,59]. Moreover, the contribution of the stomach to first pass metabolism (FPM) is known to be much smaller than the liver [55]. Therefore, the involvement of ADH4 in alcohol metabolism may be small even in FPM. 13. Physiological Roles of ADH3 and Alcohol-Related Diseases It goes without saying that ADHs essentially exist in human body to carry out physiological metabolisms, aside from their ability to metabolize the alcohol that a person imbibes. In fact, they play important roles in the metabolism of physiological alcohol and aldehyde derivatives, such as neurotransmitters with active amines (dopamine [60], norepinephrine [61], serotonin [62] etc.), cholesterols [63], steroids [64,65], bile acids [66], and Vitamin A [67]. ADH 3, in particular, is found in all living organisms as the ancestor of other forms of ADH, and is considered to play an important role in basic cell metabolism [68]. For example, ADH3 is identical to glutathione-dependent formaldehyde dehydrogenase (GSH/FADH) [69], which is the enzyme responsible for detoxifying formaldehyde in the body [26]. In addition, the s-nitrosoglutathion (GSNO) reductase activity of ADH3 plays a key role in NO metabolism [70]. ADH3 may also be involved in anti-inflammatory, anti-allergic reactions and blood pressure by metabolizing 20-OH leukotriene B4 [71] and other ω-OH fatty acids [72]. Moreover, all ADH isozymes oxidize retinol (Vitamin A), and ethanol strongly inhibits this activity [73]. Deltour et al. considered the inhibition of retinoic acid synthesis by ethanol to be a potential mechanism for fetal alcohol syndrome (FAS) [74]. Retinoic acid, the metabolite of Vitamin A, plays an important role in the neural development of vertebrates [75]. Molotkov et al. have demonstrated that ADH3 is a key enzyme in the systemic metabolism of Vitamin A, although it shows little activity for Vitamin A in vitro [67]. It also regulates the content of retinoic acid in the brain, because it is the sole ADH in the brain [23,42]. So, it seems that FAS, which is accompanied by various neuronal abnormalities, arises because ethanol inhibits retinol metabolism through ADH3 inhibition in an embryo or a fetus brain. Thus, ADH3 is a multifunctional house-keeping enzyme with