title: Dominance of the inactive Asian variant over activity and protein contents of mitochondrial aldehyde dehydrogenase 2 in human liver.
abstract: BACKGROUND
  It has been well documented that a variant allele of mitochondrial aldehyde dehydrogenase 2 (ALDH2), ALDH2*2, commonly occurs in East Asians but rarely in other ethnic populations. This unique allelic variation significantly influences drinking behavior and susceptibility to development of alcoholism. Previous structural, functional, and cellular studies indicate that the resulting variant polypeptide subunit K (Lys-487) exerts dominance of null activity and shorter half-life over the tetrameric enzyme molecules in distinct manners. However, the in vivo evidence for the proposed dominance mechanisms remains lacking.
  
  
  METHODS
  To address this question, we investigated 33 surgical liver samples identified to be normal homozygous ALDH2*1/*1 (n = 17), heterozygous ALDH2*1/*2 (n = 13), and variant homozygous ALDH2*2/*2 (n = 3). The ALDH2 activity was determined at a sufficient low acetaldehyde concentration (3 μM) and the isozyme protein amount by immunotitration using purified class-specific antibodies.
  
  
  RESULTS
  The tissue ALDH2 activity in heterozygotes was 17% that of the ALDH2*1/*1 genotype (p < 0.001), whereas the activity of ALDH2*2/*2 was too low to be precisely determined. The protein amounts of tissue ALDH2 in variant homozygotes and heterozygotes were similar but only 30 to 40% that of normal homozygotes (p < 0.01). Linear regression analyses show that ALDH2 activities were significantly correlated with the protein contents in normal homozygotes and heterozygotes, respectively (p < 0.005). The specific activity of ALDH2 per enzyme protein in ALDH2*1/*2 was 38% that of ALDH2*1/*1 (p < 0.001).
  
  
  CONCLUSIONS
  These results are in good agreement with those predicted by the model studies, thus providing in vivo evidence for differential impairments of hepatic acetaldehyde oxidation with alcohol metabolism in individuals carrying ALDH2*1/*2 and ALDH2*2/*2 genotypes.
authors.affiliation: Department of Nursing , Chang Gung University of Science and Technology, Taoyuan, Taiwan.
authors.forename: Ching-Long
authors.initials: CL
authors.lastname: Lai
authors.forename: Chung-Tay
authors.initials: CT
authors.lastname: Yao
authors.forename: Gar-Yang
authors.initials: GY
authors.lastname: Chau
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yang
authors.forename: Tai-Yu
authors.initials: TY
authors.lastname: Kuo
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Chiang
authors.forename: Shih-Jiun
authors.initials: SJ
authors.lastname: Yin
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000483:Alleles; D044466:Asian People / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005799:Genes, Dominant; D006580:Genetic Carrier Screening / Q000379:methods; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008930:Mitochondria, Liver / Q000201:enzymology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*
chemical_list: D024101:Mitochondrial Proteins; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: Acetaldehyde; Alcoholism; Aldehyde Dehydrogenase 2; Allelic Variation and Dominance; Human Liver