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Gene Review

ADH4  -  alcohol dehydrogenase 4 (class II), pi...

Homo sapiens

Synonyms: ADH-2, Alcohol dehydrogenase 4, Alcohol dehydrogenase class II pi chain, HEL-S-4
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Disease relevance of ADH4


Psychiatry related information on ADH4

  • Using rigorous study designs that account for possible population stratification, these findings confirm and extend our original observations indicating that variation at ADH4 predisposes to alcohol and drug dependence [3].
  • Dramatic decreases in class II liver ADH activity (ADH-4, or pi-ADH) were observed within 4 weeks after the start of alcohol feeding, and a shift in liver class I isozymes was found during the later stages of alcohol consumption [4].
  • The personality traits of agreeableness and extraversion are related to ADH4 polymorphism [5].

High impact information on ADH4

  • There was strong evidence that variations in ADH4 are associated with alcoholism: 12 SNPs were significantly associated [6].
  • Interestingly, the cytosolic alcohol dehydrogenase 4 failed to efficiently catalyze 9-cis-retinol oxidation [7].
  • These findings suggest that ADH4 genotypes predispose to alcohol dependence and drug dependence in a recessive manner, a predisposition that is population specific [8].
  • The genotype frequency distributions of ADH4 markers were in HWE in EA controls, but were in Hardy-Weinberg disequilibrium (HWD) (ie, deviation from HWE) in EA cases [8].
  • Significant differences between EA cases and controls were seen for genotype (10(-6)<global p<0.044), but not any allele or haplotype, frequency distributions for all seven ADH4 markers [8].

Biological context of ADH4

  • No DNA structures homologous to the glucocorticoid-responsive elements (GRE) present in the ADH2 gene were found in the upstream region of the ADH4 gene, but two structures with a 70% identity to the GRE consensus sequence were found at nonhomologous locations [9].
  • Here we report the results of systematic screening for single-nucleotide polymorphisms (SNPs) in the ADH4 gene by means of direct sequencing combined with a polymerase chain reaction method [10].
  • The human alcohol dehydrogenase 4 (ADH4) gene encodes the class II ADH4 pi subunit, which contributes to the metabolization of a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products [10].
  • Structured association analysis demonstrated that the genotypes of six ADH4 markers were associated with alcohol dependence, and all seven ADH4 markers were associated with drug dependence (P=10-0.047) [3].
  • Furthermore, docking of all retinols was more favorable in the active site of ADH4 rather than ADH1B as measured by force field and contact scores [11].

Anatomical context of ADH4

  • The ADH4 gene, which encodes human pi-alcohol dehydrogenase, is expressed in a tissue-specific manner, with the highest level in liver and lower levels in the gastrointestinal tract [2].
  • The distinct kinetics of ADH4 with 11-cis-retinol, its wide specificity with retinol isomers and its immunolocalization in several retinal cell layers, including pigment epithelium, support a role of this enzyme in the various retinol oxidations that occur in the retina [12].

Associations of ADH4 with chemical compounds

  • Here, new restriction fragment length polymorphisms (RFLPs) are described for the genes of two other classes, ADH4 (pi) and ADH5 (chi or formaldehyde dehydrogenase, FDH) [13].
  • For gastric mucosal-alcohol clearance, the relative contributions of ADH1C allozymes and ADH4 were converse as ethanol concentration increased [14].
  • ADH4 is solely extrahepatically expressed and is probably involved in first pass metabolism of ethanol beside its role in retinol metabolism [15].
  • By these criteria, all-trans-retinol, 4-oxo-retinol, and 4-hydroxy-retinol were successfully docked to both ADH1B and ADH4 [11].
  • Cytosolic ADH4 activity may complement the isomer-specific microsomal enzymes involved in photopigment regeneration and retinoic acid synthesis [12].

Other interactions of ADH4

  • Our results show an association between a certain ADH4 (formerly known as ADH7 in humans) allele and PD [16].
  • Also, genetic deficiency of both ADH1 and ADH4 does not have additive effects, verifying separate roles for these enzymes in retinoid metabolism [17].


  1. Immunochemical features in the classification of human alcohol dehydrogenase family. Lee, S.P., Chiang, C.P., Lee, S.L., Hsia, Y.J., Chuang, T.L., Lin, J.C., Liang, S.C., Nieh, S., Yin, S.J. Alcohol (2006) [Pubmed]
  2. Function of cis-acting elements in human alcohol dehydrogenase 4 (ADH4) promoter and role of C/EBP proteins in gene expression. Li, M., Edenberg, H.J. DNA Cell Biol. (1998) [Pubmed]
  3. ADH4 gene variation is associated with alcohol and drug dependence: results from family controlled and population-structured association studies. Luo, X., Kranzler, H.R., Zuo, L., Yang, B.Z., Lappalainen, J., Gelernter, J. Pharmacogenet. Genomics (2005) [Pubmed]
  4. Baboon alcohol dehydrogenase isozymes: phenotypic changes in liver following chronic consumption of alcohol. Holmes, R.S., VandeBerg, J.L. Isozymes Curr. Top. Biol. Med. Res. (1987) [Pubmed]
  5. Personality traits of agreeableness and extraversion are associated with ADH4 variation. Luo, X., Kranzler, H.R., Zuo, L., Wang, S., Gelernter, J. Biol. Psychiatry (2007) [Pubmed]
  6. Association of alcohol dehydrogenase genes with alcohol dependence: a comprehensive analysis. Edenberg, H.J., Xuei, X., Chen, H.J., Tian, H., Wetherill, L.F., Dick, D.M., Almasy, L., Bierut, L., Bucholz, K.K., Goate, A., Hesselbrock, V., Kuperman, S., Nurnberger, J., Porjesz, B., Rice, J., Schuckit, M., Tischfield, J., Begleiter, H., Foroud, T. Hum. Mol. Genet. (2006) [Pubmed]
  7. Biosynthesis of 9-cis-retinoic acid in vivo. The roles of different retinol dehydrogenases and a structure-activity analysis of microsomal retinol dehydrogenases. Tryggvason, K., Romert, A., Eriksson, U. J. Biol. Chem. (2001) [Pubmed]
  8. ADH4 gene variation is associated with alcohol dependence and drug dependence in European Americans: results from HWD tests and case-control association studies. Luo, X., Kranzler, H.R., Zuo, L., Lappalainen, J., Yang, B.Z., Gelernter, J. Neuropsychopharmacology (2006) [Pubmed]
  9. Cloning and characterization of the human ADH4 gene. von Bahr-Lindström, H., Jörnvall, H., Höög, J.O. Gene (1991) [Pubmed]
  10. Thirteen single-nucleotide polymorphisms (SNPs) in the alcohol dehydrogenase 4 (ADH4) gene locus. Iida, A., Saito, S., Sekine, A., Kondo, K., Mishima, C., Kitamura, Y., Harigae, S., Osawa, S., Nakamura, Y. J. Hum. Genet. (2002) [Pubmed]
  11. Molecular docking studies on interaction of diverse retinol structures with human alcohol dehydrogenases predict a broad role in retinoid ligand synthesis. Foglio, M.H., Duester, G. Biochim. Biophys. Acta (1999) [Pubmed]
  12. The specificity of alcohol dehydrogenase with cis-retinoids. Activity with 11-cis-retinol and localization in retina. Martras, S., Alvarez, R., Martínez, S.E., Torres, D., Gallego, O., Duester, G., Farrés, J., de Lera, A.R., Parés, X. Eur. J. Biochem. (2004) [Pubmed]
  13. Alcohol dehydrogenase genes: restriction fragment length polymorphisms for ADH4 (pi-ADH) and ADH5 (chi-ADH) and construction of haplotypes among different ADH classes. Edman, K., Maret, W. Hum. Genet. (1992) [Pubmed]
  14. Functional assessment of human alcohol dehydrogenase family in ethanol metabolism: significance of first-pass metabolism. Lee, S.L., Chau, G.Y., Yao, C.T., Wu, C.W., Yin, S.J. Alcohol. Clin. Exp. Res. (2006) [Pubmed]
  15. Mammalian alcohol dehydrogenase - functional and structural implications. Höög, J.O., Hedberg, J.J., Strömberg, P., Svensson, S. J. Biomed. Sci. (2001) [Pubmed]
  16. Alcohol dehydrogenase alleles in Parkinson's disease. Buervenich, S., Sydow, O., Carmine, A., Zhang, Z., Anvret, M., Olson, L. Mov. Disord. (2000) [Pubmed]
  17. Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid. Duester, G., Mic, F.A., Molotkov, A. Chem. Biol. Interact. (2003) [Pubmed]
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