Polymorphism of Aldehyde Dehydrogenase and Alcohol Sensitivity

Abstract

The metabolism of acetaldehyde has received considerable attention in the past years owing to its acute and chronic toxic effects in humans. Aldehyde dehydrogenase (ALDH) catalyzes the oxidation of acetaldehyde in liver and other organs. Two major isozymes of hepatic ALDH (ALDH I or E(2) and ALDH II or E(1)), which differ in their structural and functional properties, have been characterized in humans. The ALDH I with a low K(m) for acetaldehyde is predominantly of mitochondrial origin and ALDH II which has a relatively higher K(m) is of cytosolic origin. An inherited deficiency of ALDH I isozyme has been found among Japanese and Chinese which is primarily responsible for producing acute alcohol sensitivity symptoms (flushing response) after drinking mild doses of alcohol. Biochemical, immunochemical and molecular genetics data indicate a structural mutation in the ALDH I isozyme gene responsible for the loss in catalytic activity. Population genetic studies indicate a wide prevalence of this ALDH polymorphism among individuals of Mongoloid race. Flushing response to alcohol shows familial resemblances and preliminary family data from Japan, China and Korea hint to an autosomal codominant inheritance for ALDH I isozyme deficiency. The ALDH polymorphism is apparently responsible for the low incidence of alcoholism in Japanese, Chinese and Koreans. Alcohol-induced sensitivity due to ALDH isozyme deficiency may act as an inhibitory factor against excessive alcohol drinking thereby imparting a protection against alcoholism.

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

“…However, ALDH2*2 homozygotes are nearly absolutely protected against alcoholism, presumably because of the severity of their flushing (Higuchi et al 1994;Chao, 1995). This phenomenon has been observed in other countries (China and Pacific islands; Agarwal et al 1981;Goedde et al 1983Goedde et al , 1989Goedde & Agarwal, 1987) with a somewhat different prevalence of the ALDH2*2 allele, as well as in Asians living in Canada, suggesting that the flush reaction is protective against alcoholism for biochemical rather than cultural reasons (Tu & Israel, 1995).…”

Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant.

“…Mitochondrial aldehyde dehydrogenase (EC 1.2.1.3; hereafter referred to as ALDH2)' is a tetrameric protein that catalyzes the NAD+-dependent oxidation of acetaldehyde and other aliphatic aldehydes (1). Although there are multiple forms of ALDH in liver, the mitochondrial enzyme, encoded by the ALDH2 locus on chromosome 12 (2,3), has a very low Km for acetaldehyde (-1 gM) and is believed to be responsible for the oxidation of most of the acetaldehyde generated during alcohol metabolism.…”

Daidzin: a potent, selective inhibitor of human mitochondrial aldehyde dehydrogenase.

“…by the fact that in 50%o' of Asians, liver ALDH-I is present as a catalytically inactive genetic variant of this enzyme (2). The capacity of individuals with this trait to metabolize acetaldehyde is markedly impaired (3) as signaled by facial flushing soon after ingestion of ethanol (4).…”