Dominance of the Inactive Asian Variant Over Activity and Protein Contents of Mitochondrial Aldehyde Dehydrogenase 2 in Human Liver. (1st August 2013)

• Record Type: Journal Article
• Authors: Lai, Ching‐Long; Yao, Chung‐Tay; Chau, Gar‐Yang; Yang, Li‐Fang; Kuo, Tai‐Yu; Chiang, Chien‐Ping; Yin, Shih‐Jiun
• Is Part Of: Alcoholism. Volume 38:Number 1(2014:Jan.)
• Page Start: 44
• Page End: 50
• Publication Date: 2013-08-01
• Subjects: Alcoholism -- Periodicals; Alcoholism -- Periodicals; Alcoolisme; Electronic journals; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.861005
• DOI: 10.1111/acer.12215
• Languages: English
• ISSNs: 0145-6008

Abstract

<abstract abstract-type="main" id="acer12215-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="acer12215-sec-0001" sec-type="section"> <title>Background</title> <p>It has been well documented that a variant allele of mitochondrial aldehyde dehydrogenase 2 (ALDH2), <italic>ALDH2*2</italic>, 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.</p> </sec> <sec id="acer12215-sec-0002" sec-type="section"> <title>Methods</title> <p>To address this question, we investigated 33 surgical liver samples identified to be normal homozygous <italic>ALDH2*1/*1</italic> (<italic>n </italic>=<italic> </italic>17), heterozygous <italic>ALDH2*1/*2</italic> (<italic>n </italic>=<italic> </italic>13), and variant homozygous <italic>ALDH2*2/*2</italic> (<italic>n </italic>=<italic> </italic>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.</p> </sec> <sec id="acer12215-sec-0003" sec-type="section"> <title>Results</title> <p>The tissue ALDH2 activity in heterozygotes was 17% that of the <italic>ALDH2*1/*1</italic> genotype (<italic>p </italic><<italic> </italic>0.001), whereas the activity of <italic>ALDH2*2/*2</italic> 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 (<italic>p </italic><<italic> </italic>0.01). Linear regression analyses show that ALDH2 activities were significantly correlated with the protein contents in normal homozygotes and heterozygotes, respectively (<italic>p </italic><<italic> </italic>0.005). The specific activity of ALDH2 per enzyme protein in <italic>ALDH2*1/*2</italic> was 38% that of <italic>ALDH2*1/*1</italic> (<italic>p </italic><<italic> </italic>0.001).</p> </sec> <sec id="acer12215-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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 <italic>ALDH2*1/*2</italic> and <italic>ALDH2*2/*2</italic> genotypes.</p> </sec> </abstract>