Abstract
Inactive aldehyde dehydrogenase-2 (ALDH2) is a well-known biological deterrent of heavy drinking among Asians, although some individuals who have inactive ALDH2 do become alcoholics. Unknown biological mechanisms facilitating the development of the disease may operate in such a way that these individuals overcome adverse reactions, or they may lower the intensity of the reactions. To examine our hypothesis that ethanol-oxidizing isoenzymes have lower catalytic properties in some persons, we investigated polymorphisms of ethanol-oxidizing enzymes that may alter their catalytic activities, viz., alcohol dehydrogenase-2 (ADH2) and −3 (ADH3), and cytochrome P450 2E1 (CYTP2E1), among 80 Japanese alcoholics with inactive ALDH2, 575 alcoholics with active ALDH2, and 461 controls. Although higher ADH2*1 and ADH3*2 allele frequencies were observed in alcoholics than in controls, there was no significant difference in ADH2 and ADH3 genotypes between alcoholics with inactive ALDH2 and alcoholics with active ALDH2. The genotype distributions of CYTP2E1 did not differ among the three groups, indicating no allelic association of the c1/c2 polymorphism of CYTP2E1 with alcoholism. These results suggest that genetic variations in ethanol-oxidizing activities are involved in the development of the disease, but that these variations are not specific in alcoholics with inactive ALDH2, a group at genetically low risk for alcoholism.
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References
American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders, 3rd edn revised. American Psychiatric Association, Washington, DC
Badger TM, Huang J, Ronis M, Lumpkin CK (1993) Induction of cytochrome P450 2E1 during chronic ethanol exposure occurs via transcription of the CYP 2E1 gene when blood alcohol concentrations are high. Biochem Biophys Res Commun 190:780–785
Bosron WF, Li T-K (1986) Genetic polymorphism of human liver alcohol and aldehyde dehydrogenase, and their relationship to alcohol metabolism and alcoholism. Hepatology 6:502–510
Bosron WF, Li T-K (1988) Catalytic and structural properties of the human liver ββ alcohol dehydrogenase isoenzymes. In: Kuriyama K, Takada A, Ishii H (eds) Biomedical and social aspects of alcohol and alcoholism. Elsevier, Amsterdam, pp 31–34
Bosron WF, Magnes LJ, Li T-K (1983) Kinetic and electrophoretic properties of native and recombined isoenzymes of human liver alcohol dehydrogenase. Biochemistry 22:1852–1857
Carr LG, Hartleroad JY, Liang Y, Mendenhall C, Moritz T, Thomasson H (1995) Polymorphism at the P450IIE1 locus is not associated with alcoholic liver disease in Caucasian men. Alcoholism 19:182–184
Crabb DW, Edenberg HJ, Bosron WF, Li T-K (1989) Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity: the inactive ALDH22 allele is dominant. J Clin Invest 83:314–316
Gonzalez FJ, Ueno T, Umeno M, Song BJ, Veech RL, Gelboin HV (1991) Microsomal ethanol oxidizing system: transcriptional and posttranscriptional regulation of cytochrome P450, CYP2E1. Alcohol Alcohol 26 (Suppl 1):97–101
Harada S, Agarwal DP, Goedde HW (1982) Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in Japanese. Lancet 11:827
Harada S, Zhang S (1993) New strategy for detection of ALDH2 mutant. Alcohol Alcohol 28:11–13
Hayashi S, Watanabe J, Kawajiri K (1991) Genetic polymorphisms in the 5′-flanking region change transcriptional regulation of the human cytochrome P450 IIE1 gene. J Biochem (Tokyo) 110:559–565
Higuchi S (1996) Polymorphisms of ethanol metabolizing enzyme genes and alcoholism. Alcohol Alcohol (in press)
Higuchi S, Muramatsu T, Shigemori K, Saito M, Kono H, Dufour MC, Harford TC (1992) The relationship between low Km aldehyde dehydrogenase phenotype and drinking behavior in Japanese. J Stud Alcohol 53:170–175
Higuchi S, Matsushita S, Imazeki H, Kinoshita T, Takagi S, Kono H (1994) Aldehyde dehydrogenase genotypes in Japanese alcoholics. Lancet 343:741–742
Mizoi Y, Tatsuno Y, Adachi J, Kogame M, Fukunaga T, Fujiwara S, Hishida S, Ijiri I (1983) Alcohol sensitivity related to polymorphism of alcohol-metabolizing enzymes in Japanese. Pharmacol Biochem Behav 18 (Suppl 1):127–133
Muramatsu T, Wang Z-C, Fang Y-R, Hu K-B, Heqin Y, Yamada K, Higuchi S, Harada S, Kono H (1995) Alcohol and aldehyde dehydrogenase genotyping and drinking behavior of Chinese living in Shanghai. Hum Genet 96:151–154
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
SAS Institute (1985) SAS user's guide: basic, version 5. SAS Institute, Cary, NC
Takeshita T, Morimoto K, Mao XQ, Hashimoto T, Furuyama J (1994) Characterization of the three genotypes of low Km aldehyde dehydrogenase in a Japanese population. Hum Genet 94:217–223
Thomasson HR, Edenberg HJ, Crabb DW, Mai X-L, Jerome RE, Li T-K, Wang S-P, Lin Y-T, Lu R-B, Yin S-J (1991) Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet 48:677–681
Thomasson HR, Crabb DW, Edenberg HJ, Li T-K (1993) Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism. Behav Genet 23:131–136
Thomasson HR, Crabb DW, Edenberg HJ, Li T-K, Hwu H-G, Chen C-C, Yeh E-K, Yin S-J (1994) Low frequency of the ADH2*2 allele among Atayal natives of Taiwan with alcohol use disorders. Alcoholism 18:640–643
Xu Y, Carr LG, Bosron WF, Li T-K, Edenberg HJ (1988) Genotyping of human alcohol dehydrogenases at the ADH2 and ADH3 loci following DNA sequence amplification. Genomics 2:209–214
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Higuchi, S., Muramatsu, T., Matsushita, S. et al. Polymorphisms of ethanol-oxidizing enzymes in alcoholics with inactive ALDH2. Hum Genet 97, 431–434 (1996). https://doi.org/10.1007/BF02267061
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DOI: https://doi.org/10.1007/BF02267061