Alcohol Sensitivity, Acute

A number sign (#) is used with this entry because acute alcohol sensitivity can be caused by mutation in the ALDH2 gene (100650).

Clinical Features

Wolff (1972) demonstrated that East Asians, after drinking amounts of alcohol that have no detectable effect on Caucasians, respond with marked facial flushing and mild to moderate symptoms of intoxication. Wolff (1972) believed that group differences were attributable to differences in autonomic reactivity.

Stamatoyannopoulos et al. (1975) suggested that the racial difference in alcohol intoxication is due to rapid acetaldehyde formation as a result of the highly active atypical alcohol dehydrogenase isozyme found in high frequency in East Asians.

Goedde et al. (1979) proposed that the high frequency of acute alcoholic intoxication in East Asians is related to the high frequency of persons with absence of ALDH2 liver isozyme. Individuals lacking the enzyme suffer the alcohol-flush reaction when they drink alcoholic beverages. Goedde et al. (1979) suggested that the reaction is the result of excessive acetaldehyde accumulation, and the unpleasant symptoms tend to reduce alcohol consumption. The lower incidence of alcoholism in certain East Asian groups may have its basis in these observations.

Almost all Caucasians have 2 major ALDH isozymes in the liver: cytosolic ALDH1 (100640) and mitochondrial ALDH2. Harada et al. (1980) presented evidence that aldehyde dehydrogenase is polymorphic in Japanese. As in previous studies in Europeans, they found 2 isozymes of ALDH in liver specimens of Japanese, but unlike the study of specimens of Europeans, they found that 52% of Japanese specimens showed absence of ALDH2. The authors suggested that the intoxicating symptoms after alcohol drinking in many Japanese may be due to delayed oxidation of acetaldehyde. The lack of ALDH2 is apparently responsible for the higher blood acetaldehyde levels in East Asians, leading to facial flushing and other vasomotor symptoms after alcohol intake.

Agarwal et al. (1981) performed a population genetic study in Asians of several different extractions. They investigated ALDH isozymes in hair root lysates with a sensitive isoelectric focusing method. Between 40 and 80% of the several Asian groups were found to be deficient in ALDH2, whereas not a single European individual was deficient. Deficiency was invariably associated with sensitivity to alcohol. Family studies suggested autosomal recessive inheritance of the deficiency. Harada et al. (1981) found the deficiency in 43% of Japanese; all deficient persons had flushing symptoms and, after alcohol drinking, showed a mean concentration of acetaldehyde of 37.3 micromoles as compared with 2.1 micromoles in nondeficient persons.

Impraim et al. (1982) found that the livers of persons lacking the ALDH2 isozyme show an enzymatically inactive but immunologically cross-reactive material (CRM) corresponding to the ALDH2 isozyme.

Goedde et al. (1983) showed that the frequency of absent ALDH2 varied from 69% in Indians of the Ecuador Highlands to 44% in Japanese and 35% in Chinese to 0% in Egyptians, Liberians, Kenyans, and Europeans. They suggested that deficiency is related to flushing and a slower metabolism of acetaldehyde, and in turn a lower frequency of alcoholism and alcohol-related problems.

The ALDH2 alleles encoding the active and inactive subunits are termed 'ALDH2*1' and 'ALDH2*2,' respectively; see 100650.0001. It had been thought that the 2 alleles were expressed codominantly, and that only individuals homozygous for ALDH2*2 were ALDH2-deficient. However, studies of the inheritance of alcohol-induced flushing in families suggested that the trait is dominant (Schwitters et al., 1982).

Shibuya et al. (1988) studied 23 Japanese with alcoholic liver disease. No difference was found in the genotypes at the ADH2 (103720) locus; however, at the ALDH2 locus, 20 of the 23 patients were homozygous for ALDH2*1, only 3 were heterozygous, and none of the patients was homozygous for ALDH2*2. The results were interpreted as indicating that Japanese with the atypical allele are at a much lower risk for alcoholic liver disease, presumably due to their sensitivity to alcohol intoxication.

In a study of 140 men and women of Chinese, Japanese, and Korean heritage, Wall et al. (2000) found that those with ALDH2*2 alleles experienced more severe hangovers and suggested that this may contribute, in part, to protection against the development of excessive or problematic drinking in Asian Americans. Yokoyama et al. (2005) found that inactive heterozygous ALDH2, alcohol flushing, and increased mean corpuscular volume (MCV) were positively associated with hangover susceptibility in Japanese workers, suggesting that acetaldehyde is etiologically linked to the development of hangover.

Yoshida et al. (1989) demonstrated that among Caucasians alcohol flushing can be related to abnormalities of ALDH1. In 9 unrelated Caucasian alcohol flushers, they found 1 who exhibited low activity (10-20% of normal) and another who exhibited moderately low activity (60%) and altered kinetic properties. The electrophoretic mobilities of these 2 samples were not altered. Immunologic quantitation indicated that the amount of protein in the 2 samples was not reduced in parallel with the enzyme deficiency. In the first case, the daughter of the proposita also had very low enzyme activity and alcohol flushing.

Pathogenesis

To study the mechanism by which the ALDH2*2 allele exerts its dominant effect in decreasing ALDH2 activity in liver extracts and producing cutaneous flushing when the subject drinks alcohol, Xiao et al. (1995) cloned ALDH2*1 cDNA and generated the ALDH2*2 allele by site-directed mutagenesis. These cDNAs were transduced using retroviral vectors into HeLa and CV1 cells, which do not express ALDH2. The normal allele directed synthesis of immunoreactive ALDH2 protein with the expected isoelectric point and increased aldehyde dehydrogenase activity. The ALDH2*2 allele directed synthesis of mRNA and immunoreactive protein, but the protein lacked enzymatic activity. When ALDH2*1-expressing cells were transduced with ALDH2*2 vectors, both mRNAs were expressed and immunoreactive proteins with isoelectric points ranging between those of the 2 gene products were present, indicating that the subunits formed heteromers. ALDH2 activity in these cells was reduced below that of the parental ALDH2*1-expressing cells. Thus, the authors concluded that ALDH2*2 allele is sufficient to cause ALDH2 deficiency in vitro.

Xiao et al. (1996) referred to the ALDH2 enzyme encoded by the ALDH2*1 allele (the wildtype form) as ALDH2E and the enzyme subunit encoded by ALDH2*2 as ALDH2K. They found that the ALDH2E enzyme was very stable, with a half-life of at least 22 hours. ALDH2K, on the other hand, had an enzyme half-life of only 14 hours. In cells expressing both subunits, most of the subunits assemble as heterotetramers, and these enzymes had a half-life of 13 hours. Thus, the effect of ALDH2K on enzyme turnover is dominant. Their studies indicated that ALDH2*2 exerts its dominant effect both by interfering with the catalytic activity of the enzyme and by increasing its turnover.

Because genetic epidemiologic studies have suggested a mechanism by which homozygosity for the ALDH2*2 allele inhibits the development of alcoholism in Asians, Peng et al. (1999) recruited 18 adult Han Chinese men, matched by age, body-mass index, nutritional state, and homozygosity at the ALDH2 gene loci from a population of 273 men. Six individuals were chosen for each of the 3 ALDH2 allotypes, i.e., 2 homozygotes and 1 heterozygote. Following a low dose of ethanol, homozygous ALDH2*2 individuals were found to be strikingly responsive with pronounced cardiovascular hemodynamic effects as well as subjective perception of general discomfort for as long as 2 hours following ingestion.

Molecular Genetics

Among 71 Japanese nondrinkers and 268 drinkers of alcohol, Liu et al. (2005) found that drinkers had a significantly higher frequency of the 504glu (ALDH2*1) allele. Individuals with the 504lys (ALDH2*2; 100650.0001) allele had an increased risk of alcohol-induced flushing (odds ratio of 33.0).

History

Fenna et al. (1971) concluded that ethanol is metabolized significantly faster in whites than in Eskimos or American Indians, but Bennion and Li (1976) could find no evidence that this is the case.