Dominance of the Inactive Asian Variant Over Activity and Protein Contents of Mitochondrial Aldehyde Dehydrogenase 2 in Human Liver
Article first published online: 1 AUG 2013
Copyright © 2013 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 38, Issue 1, pages 44–50, January 2014
How to Cite
Lai, C.-L., Yao, C.-T., Chau, G.-Y., Yang, L.-F., Kuo, T.-Y., Chiang, C.-P. and Yin, S.-J. (2014), Dominance of the Inactive Asian Variant Over Activity and Protein Contents of Mitochondrial Aldehyde Dehydrogenase 2 in Human Liver. Alcoholism: Clinical and Experimental Research, 38: 44–50. doi: 10.1111/acer.12215
- Issue published online: 21 JAN 2014
- Article first published online: 1 AUG 2013
- Manuscript Accepted: 9 MAY 2013
- Manuscript Received: 16 MAR 2013
- National Science Council. Grant Numbers: 99-2320-B016-003-MY2, 90-2320-B016-057, 89-2320-B016-098
- National Health Research Institutes. Grant Number: EX91-8939BP
- Aldehyde Dehydrogenase 2;
- Human Liver;
- Allelic Variation and Dominance;
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.
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.
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).
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.