Relationship Between Genetic Polymorphisms of Alcohol-Metabolizing Enzymes and Changes in Risk Factors for Coronary Heart Disease Associated with Alcohol Consumption (Lipids, Lipoproteins, And Cardiovascular Risk Factors‪)‬

Epidemiologic studies have consistently shown that light or light to moderate drinkers are at a lower risk of coronary heart disease (CHD) [3] (1-6). The mechanisms of this association include beneficial effects on HDL- and LDL-cholesterol, insulin sensitivity, platelet aggregation, blood coagulation, and fibrinolysis (1-7). However, drinking also has negative effects on blood pressure (8), triglycerides (9), and uric acid (10). These effects could attenuate the cardioprotective effect of alcohol. A recent study suggested that the extent of the negative effects of drinking varied on an individual basis (11). Although the mechanism of this variability is not clear, it may be mediated partly by the speed of alcohol metabolism, the types of alcoholic beverages, the regularity of drinking, and nutritional status. The major enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) (12). ADH, which metabolizes ethanol to acetaldehyde, is a dimeric protein consisting of two active subunts, and six ADH genes have been characterized (13). Among them, the ADH2 and ADH3 loci are polymorphic. The ADH2 locus has three alleles: [ADH2.sup.1], which encodes for the [[beta].sup.1] subunit with low activity; [ADH2.sup.2], which encodes for the [[beta].sup.2] subunit with high activity; and ADH23, which encodes for the [[beta].sup.3] subunit, which is rarely expressed in Japanese (12). The ADH3 locus has two alleles: [ADH3.sup.1], which encodes for the [[gamma].sup.1] subunit; and [ADH3.sup.2], which encodes for the [[gamma].sup.2] subunit. Because the difference in kinetic properties is much smaller between the [[gamma].sup.1] and [[gamma].sup.2] subunits than between the [[beta].sup.1] and [[beta].sup.2] subunits, the ADH2 gene polymorphism could play an important role in individual variations regarding ethanol elimination (12). On the other hand, ALDH, which converts acetaldehyde to acetate, also has multiple forms. Among them, ALDH2, with a low [K.sub.m], is thought to be responsible for most acetaldehyde oxidation (12). The [ALDH2.sup.1] and [ALDH2.sup.2] genes encode the active and the inactive subunit, respectively (14,15); therefore, the [ALDH2.sup.2] gene contributes to the manifestations of increased blood acetaldehyde after alcohol drinking, e.g., facial flushing, palpitations, and nausea (16,17).