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Dominance of the Inactive Asian Variant Over Activity and Protein Contents of Mitochondrial Aldehyde Dehydrogenase 2 in Human Liver
Author(s) -
Lai ChingLong,
Yao ChungTay,
Chau GarYang,
Yang LiFang,
Kuo TaiYu,
Chiang ChienPing,
Yin ShihJiun
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12215
Subject(s) - aldh2 , aldehyde dehydrogenase , heterozygote advantage , dominance (genetics) , isozyme , allele , biology , genotype , protein subunit , acetaldehyde , genetics , enzyme , microbiology and biotechnology , biochemistry , gene , ethanol
Background It has been well documented that a variant allele of mitochondrial aldehyde dehydrogenase 2 ( ALDH 2), ALDH 2*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 ALDH 2*1/*1 ( n = 17), heterozygous ALDH 2*1/*2 ( n = 13), and variant homozygous ALDH 2*2/*2 ( n = 3). The ALDH 2 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 ALDH 2 activity in heterozygotes was 17% that of the ALDH 2*1/*1 genotype ( p < 0.001), whereas the activity of ALDH 2*2/*2 was too low to be precisely determined. The protein amounts of tissue ALDH 2 in variant homozygotes and heterozygotes were similar but only 30 to 40% that of normal homozygotes ( p < 0.01). Linear regression analyses show that ALDH 2 activities were significantly correlated with the protein contents in normal homozygotes and heterozygotes, respectively ( p < 0.005). The specific activity of ALDH 2 per enzyme protein in ALDH 2*1/*2 was 38% that of ALDH 2*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 ALDH 2*1/*2 and ALDH 2*2/*2 genotypes.