title: Influence of genetic variations of ethanol-metabolizing enzymes on phenotypes of alcohol-related disorders.
abstract: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2) play central roles in the metabolism of ethanol and its metabolite, acetaldehyde, in the liver. In ADH2, one nucleotide replacement causes either a super-active beta 2 subunit encoded by the ADH2*2 allele or a less active beta 1 subunit (ADH2*1 allele). In the same way, a G/A replacement at codon 487 of the ALDH2 gene produces an inactive form of the enzyme. Because the geno-types of these genes may explain individual differences in concentration and elimination of ethanol and acetaldehyde in the blood after drinking, they could be used as models to elucidate the contribution of these substances to the development of addiction and various types of organ damage. We have examined the influence of genetic variations of these enzymes on alcohol-related disorders in the Japanese. The results revealed that (1) the less active allele of the ADH2 gene (ADH2*1) is associated with an increased risk for alcohol dependence, alcohol-induced persistent amnestic disorder, alcohol withdrawal syndrome, and cancer of the upper GI tract; (2) the inactive allele of the ALDH2 gene (ALDH2*2) is associated with a decreased risk for alcohol dependence, and an increased risk for alcoholic polyneuropathy and cancer in the same region; and (3) these genetic variations modify clinical features of alcohol dependence. Possible mechanisms of altered risk for these disorders are discussed.
authors.affiliation: Institute of Clinical Research, National Alcoholism Center Kurihama Hospital, Yokosuka, Kanagawa, 239-0841, Japan. h-susumu@db3.so-net.ne.jp
authors.forename: Susumu
authors.initials: S
authors.lastname: Higuchi
authors.forename: Sachio
authors.initials: S
authors.lastname: Matsushita
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Masaki
authors.forename: Akira
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kimura
authors.forename: Go
authors.initials: G
authors.lastname: Suzuki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D019973:Alcohol-Related Disorders / Q000201:enzymology / Q000235:genetics*; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000431:Ethanol / Q000378:metabolism; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D010641:Phenotype
chemical_list: D000431:Ethanol; D000426:Alcohol Dehydrogenase; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial