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Gene Review

ALDH2  -  aldehyde dehydrogenase 2 family...

Homo sapiens

Synonyms: ALDH class 2, ALDH-E2, ALDHI, ALDM, Aldehyde dehydrogenase, mitochondrial
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Disease relevance of ALDH2


Psychiatry related information on ALDH2

  • In this study, the relationship of the ALDH2 genotype to alcohol-associated symptoms and drinking behavior was investigated in 524 Japanese workers, using a new, rapid, and nonisotopic polymerase chain reaction (PCR) method [6].
  • The aim of this study was to test the hypothesis that polymorphisms of the ADH1B and ALDH2 genes are significantly associated with genotoxicity induced by alcohol drinking, measured using the cytokinesis-block micronucleus (CBMN) assay, an established biomarker of genome instability, in peripheral blood lymphocytes of 286 healthy Japanese men [7].
  • The relationship of ethnicity to alcohol dependence was mediated by ALDH2 status and conduct disorder, although Chinese ethnicity remained significant [8].
  • METHODS: We recruited 579 Han Chinese individuals in Taiwan, intending to examine the alcoholism-protection effects of different ADH1B and ALDH2 genotypes with or without antisocial personality disorder [9].
  • Heterozygous for ALDH2 in alcohol dependence: relationship between the ALDH2 genotype and personality disorder in alcohol-dependent patients with the Flushing syndrome [10].

High impact information on ALDH2

  • Administration of ASO-9 (20 mg/kg/day for 4 d) to rats resulted in a 50% reduction in liver ALDH2 mRNA, a 40% inhibition in ALDH2 activity, and a fourfold (P < 0.001) increase in circulating plasma acetaldehyde levels after ethanol (1 g/kg) administration [11].
  • Rat hepatoma cells incubated for 24 h with an antisense oligonucleotide (ASO-9) showed reductions in ALDH2 mRNA levels of 85% and ALDH2 (half-life of 22 h) activity of 55% equivalent to a >90% inhibition in ALDH2 synthesis [11].
  • Deficiency in mitochondrial aldehyde dehydrogenase (ALDH2), a tetrameric enzyme, results from inheriting one or two ALDH2*2 alleles [12].
  • In addition to this effect on the enzyme activity, we now report that ALDH2*2 heterozygotes had lower levels of ALDH2 immunoreactive protein in autopsy liver samples [12].
  • The ALDH2*2-encoded subunit (ALDH2K) reduces the activity of ALDH2 enzyme in cell lines expressing the wild-type subunit (ALDH2E) [12].

Chemical compound and disease context of ALDH2


Biological context of ALDH2


Anatomical context of ALDH2

  • Therefore, we determined the genotypes of the ADH2, ADH3, and ALDH2 loci of alcoholic and nonalcoholic Chinese men living in Taiwan, using leukocyte DNA amplified by the PCR and allele-specific oligonucleotides [21].
  • In addition, the interaction of ALDH1 and ALDH2 may alter the retinoid metabolism in the pancreas, thereby influencing insulin secretion and precipitating diabetes [3].
  • Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms [7].
  • Western blot analysis revealed that ALDH2 is highly expressed in the heart, skeletal muscle, and brain with moderate expression in liver, eye, and swim bladder of the zebrafish [22].
  • ALDH2 expression and localisation was also determined in human skin, while ethanol oxidation, catalysed by ADH, was investigated in the mouse, guinea-pig and human skin cytosol [23].

Associations of ALDH2 with chemical compounds

  • Separation of their digests by high-performance reverse-phase chromatography and by two-dimensional paper chromatography and electrophoresis revealed that ALDH2 contained a peptide sequence of -Glu-Leu-Gly-Glu-Ala-Gly-Leu-Gln-Ala-Asn-Val-Gln-Val-Lys- and that the glutamine adjacent to lysine was substituted by lysine in CRM [17].
  • All other tryptic peptides, including eight peptides containing S-carboxymethylcysteine, were common in ALDH2 and CRM [17].
  • Polymorphisms have been observed at two of the five loci encoding alcohol dehydrogenase subunits: ADH2 (producing three beta subunits) and ADH3 (producing two tau subunits) and also at the locus encoding the metabolically important form of aldehyde dehydrogenase, ALDH2 [2].
  • The aim of this study was to evaluate zebrafish (Danio rerio) as a model for ethanol metabolism by cloning, expressing, and characterizing the zebrafish ALDH2 [22].
  • Moreover, the ADH1B and ALDH2 genes might be involved in dopamine metabolism [24].
  • The impact of ALDH2 Lys+ with ADH2 Arg+ was more evident in low folate consumer (OR = 2.32, 1.19-4.55) than high folate consumer (OR 1.38, 0.80-2.38) [25].

Physical interactions of ALDH2


Regulatory relationships of ALDH2

  • The frequency of the inactive ALDH2 genotype was higher than that in the normal control subjects (P < 0.002) and that in the NIDDM control subjects (P < 0.003) [3].
  • However, the ADH2 genotype did not seem to influence drinking frequency or amounts of alcohol intake in each ALDH2 genotype [29].
  • The ALDH2 FP330-3' site appears to represent a complex nuclear receptor response element that is activated by RXRs and HNF-4 but repressed by members of the COUP-TF family [30].
  • GTN (1 microM) inhibited ALDH2 activity (55 +/- 6% of control) and ablated ALDH3 activity [31].

Other interactions of ALDH2

  • Allelic variation at alcohol metabolism genes ( ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population [32].
  • The results of this study have identified important novel associations between ADH1B/ALDH2 polymorphisms and genotoxicity in alcohol drinkers [7].
  • CYP2E1 and ALDH2 genotypes and alcohol dependence in Japanese [33].
  • Therefore, association studies of alcoholism in Chinese Han might be more sensitive if controlled for the genotypes of ADH2,ADH3, and ALDH2, when other loci, such as DRD2, are examined [34].
  • Neither MTHFR C677T nor ALDH2 showed a measurable association with colorectal adenoma [35].

Analytical, diagnostic and therapeutic context of ALDH2


  1. Alcoholism and alcoholic organ damage and genetic polymorphisms of alcohol metabolizing enzymes in Chinese patients. Chao, Y.C., Young, T.H., Tang, H.S., Hsu, C.T. Hepatology (1997) [Pubmed]
  2. Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage. Day, C.P., Bashir, R., James, O.F., Bassendine, M.F., Crabb, D.W., Thomasson, H.R., Li, T.K., Edenberg, H.J. Hepatology (1991) [Pubmed]
  3. Mitochondrial aldehyde dehydrogenase in diabetes associated with mitochondrial tRNA(Leu(UUR)) mutation at position 3243. Suzuki, Y., Muramatsu, T., Taniyama, M., Atsumi, Y., Suematsu, M., Kawaguchi, R., Higuchi, S., Asahina, T., Murata, C., Handa, M., Matsuoka, K. Diabetes Care (1996) [Pubmed]
  4. Genetic polymorphisms of ADH2, ADH3, CYP4502E1 Dra-I and Pst-I, and ALDH2 in Spanish men: lack of association with alcoholism and alcoholic liver disease. Vidal, F., Lorenzo, A., Auguet, T., Olona, M., Broch, M., Gutiérrez, C., Aguilar, C., Estupiñà, P., Santos, M., Richart, C. J. Hepatol. (2004) [Pubmed]
  5. Chaperonin GroESL mediates the protein folding of human liver mitochondrial aldehyde dehydrogenase in Escherichia coli. Lee, K.H., Kim, H.S., Jeong, H.S., Lee, Y.S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  6. Characterization of the three genotypes of low Km aldehyde dehydrogenase in a Japanese population. Takeshita, T., Morimoto, K., Mao, X., Hashimoto, T., Furuyama, J. Hum. Genet. (1994) [Pubmed]
  7. Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms. Ishikawa, H., Ishikawa, T., Yamamoto, H., Fukao, A., Yokoyama, K. Mutat. Res. (2007) [Pubmed]
  8. ALDH2 status and conduct disorder mediate the relationship between ethnicity and alcohol dependence in Chinese, Korean, and White American college students. Luczak, S.E., Wall, T.L., Cook, T.A., Shea, S.H., Carr, L.G. Journal of abnormal psychology. (2004) [Pubmed]
  9. No alcoholism-protection effects of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan. Lu, R.B., Ko, H.C., Lee, J.F., Lin, W.W., Huang, S.Y., Wang, T.J., Wu, Y.S., Lu, T.E., Chou, Y.H. Alcohol. Clin. Exp. Res. (2005) [Pubmed]
  10. Heterozygous for ALDH2 in alcohol dependence: relationship between the ALDH2 genotype and personality disorder in alcohol-dependent patients with the Flushing syndrome. Iwahashi, K. Biol. Psychiatry (1995) [Pubmed]
  11. Eliciting the low-activity aldehyde dehydrogenase Asian phenotype by an antisense mechanism results in an aversion to ethanol. Garver, E., Tu Gc, n.u.l.l., Cao, Q.N., Aini, M., Zhou, F., Israel, Y. J. Exp. Med. (2001) [Pubmed]
  12. The mutation in the mitochondrial aldehyde dehydrogenase (ALDH2) gene responsible for alcohol-induced flushing increases turnover of the enzyme tetramers in a dominant fashion. Xiao, Q., Weiner, H., Crabb, D.W. J. Clin. Invest. (1996) [Pubmed]
  13. High incidence of ADH2*1/ALDH2*1 genes among Japanese alcohol dependents and patients with alcoholic liver disease. Tanaka, F., Shiratori, Y., Yokosuka, O., Imazeki, F., Tsukada, Y., Omata, M. Hepatology (1996) [Pubmed]
  14. Aldehyde dehydrogenase 2 gene is a risk factor for myocardial infarction in Japanese men. Takagi, S., Iwai, N., Yamauchi, R., Kojima, S., Yasuno, S., Baba, T., Terashima, M., Tsutsumi, Y., Suzuki, S., Morii, I., Hanai, S., Ono, K., Baba, S., Tomoike, H., Kawamura, A., Miyazaki, S., Nonogi, H., Goto, Y. Hypertens. Res. (2002) [Pubmed]
  15. Low-Km aldehyde dehydrogenase deficiency does not influence the elevation of blood pressure by alcohol. Okayama, A., Ueshima, H., Yamakawa, M., Kita, Y. Journal of human hypertension. (1994) [Pubmed]
  16. Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Chen, C.C., Lu, R.B., Chen, Y.C., Wang, M.F., Chang, Y.C., Li, T.K., Yin, S.J. Am. J. Hum. Genet. (1999) [Pubmed]
  17. Molecular abnormality of an inactive aldehyde dehydrogenase variant commonly found in Orientals. Yoshida, A., Huang, I.Y., Ikawa, M. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  18. Diplotype trend regression analysis of the ADH gene cluster and the ALDH2 gene: multiple significant associations with alcohol dependence. Luo, X., Kranzler, H.R., Zuo, L., Wang, S., Schork, N.J., Gelernter, J. Am. J. Hum. Genet. (2006) [Pubmed]
  19. Polymorphisms in alcohol metabolizing enzyme genes and alcoholic cirrhosis in Japanese patients: a multivariate analysis. Yamauchi, M., Maezawa, Y., Mizuhara, Y., Ohata, M., Hirakawa, J., Nakajima, H., Toda, G. Hepatology (1995) [Pubmed]
  20. Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in Chinese patients. Chao, Y.C., Liou, S.R., Chung, Y.Y., Tang, H.S., Hsu, C.T., Li, T.K., Yin, S.J. Hepatology (1994) [Pubmed]
  21. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Thomasson, H.R., Edenberg, H.J., Crabb, D.W., Mai, X.L., Jerome, R.E., Li, T.K., Wang, S.P., Lin, Y.T., Lu, R.B., Yin, S.J. Am. J. Hum. Genet. (1991) [Pubmed]
  22. Molecular cloning, baculovirus expression, and tissue distribution of the zebrafish aldehyde dehydrogenase 2. Lassen, N., Estey, T., Tanguay, R.L., Pappa, A., Reimers, M.J., Vasiliou, V. Drug Metab. Dispos. (2005) [Pubmed]
  23. Species variations in cutaneous alcohol dehydrogenases and aldehyde dehydrogenases may impact on toxicological assessments of alcohols and aldehydes. Cheung, C., Davies, N.G., Hoog, J.O., Hotchkiss, S.A., Smith Pease, C.K. Toxicology (2003) [Pubmed]
  24. Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. Huang, S.Y., Lin, W.W., Ko, H.C., Lee, J.F., Wang, T.J., Chou, Y.H., Yin, S.J., Lu, R.B. Alcohol. Clin. Exp. Res. (2004) [Pubmed]
  25. A gene-gene interaction between ALDH2 Glu487Lys and ADH2 His47Arg polymorphisms regarding the risk of colorectal cancer in Japan. Matsuo, K., Wakai, K., Hirose, K., Ito, H., Saito, T., Suzuki, T., Kato, T., Hirai, T., Kanemitsu, Y., Hamajima, H., Tajima, K. Carcinogenesis (2006) [Pubmed]
  26. The role of nuclear factor NF-Y/CP1 in the transcriptional regulation of the human aldehyde dehydrogenase 2-encoding gene. Stewart, M.J., Dipple, K.M., Stewart, T.R., Crabb, D.W. Gene (1996) [Pubmed]
  27. Transcriptional control of the human aldehyde dehydrogenase 2 promoter by hepatocyte nuclear factor 4: inhibition by cyclic AMP and COUP transcription factors. You, M., Fischer, M., Cho, W.K., Crabb, D. Arch. Biochem. Biophys. (2002) [Pubmed]
  28. Purification, N-terminal sequence determination and enzymatic characterization of antiquitin from the liver of grass carp. Chan, W.M., Tang, W.K., Cheng, C.H., Fong, W.P. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. (2003) [Pubmed]
  29. Association of the ADH2 genotypes with skin responses after ethanol exposure in Japanese male university students. Takeshita, T., Yang, X., Morimoto, K. Alcohol. Clin. Exp. Res. (2001) [Pubmed]
  30. The retinoid X receptor response element in the human aldehyde dehydrogenase 2 promoter is antagonized by the chicken ovalbumin upstream promoter family of orphan receptors. Pinaire, J., Hasanadka, R., Fang, M., Chou, W.Y., Stewart, M.J., Kruijer, W., Crabb, D. Arch. Biochem. Biophys. (2000) [Pubmed]
  31. Nitrate-based vasodilators inhibit multiple vascular aldehyde dehydrogenases. Murphy, T.C., Arntzen, R., Picklo, M.J. Cardiovasc. Toxicol. (2005) [Pubmed]
  32. Allelic variation at alcohol metabolism genes ( ADH1B, ADH1C, ALDH2) and alcohol dependence in an American Indian population. Mulligan, C.J., Robin, R.W., Osier, M.V., Sambuughin, N., Goldfarb, L.G., Kittles, R.A., Hesselbrock, D., Goldman, D., Long, J.C. Hum. Genet. (2003) [Pubmed]
  33. CYP2E1 and ALDH2 genotypes and alcohol dependence in Japanese. Iwahashi, K., Matsuo, Y., Suwaki, H., Nakamura, K., Ichikawa, Y. Alcohol. Clin. Exp. Res. (1995) [Pubmed]
  34. No association between DRD2 locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population. Lee, J.F., Lu, R.B., Ko, H.C., Chang, F.M., Yin, S.J., Pakstis, A.J., Kidd, K.K. Alcohol. Clin. Exp. Res. (1999) [Pubmed]
  35. Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: Self-Defense Forces Health Study. Hirose, M., Kono, S., Tabata, S., Ogawa, S., Yamaguchi, K., Mineshita, M., Hagiwara, T., Yin, G., Lee, K.Y., Tsuji, A., Ikeda, N. Cancer Sci. (2005) [Pubmed]
  36. Differences in the isozymes involved in alcohol metabolism between caucasians and orientals. Yoshida, A. Isozymes Curr. Top. Biol. Med. Res. (1983) [Pubmed]
  37. Genetic polymorphism and activities of human lung alcohol and aldehyde dehydrogenases: implications for ethanol metabolism and cytotoxicity. Yin, S.J., Liao, C.S., Chen, C.M., Fan, F.T., Lee, S.C. Biochem. Genet. (1992) [Pubmed]
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