Combination of ADH1B*2/ALDH2*2 polymorphisms alters acetaldehyde‐derived DNA damage in the blood of Japanese alcoholics

Abstract

The acetaldehyde associated with alcoholic beverages is an evident carcinogen for the esophagus. Genetic polymorphisms of the alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genes are associated with the risk of esophageal cancer. However, the exact mechanism via which these genetic polymorphisms affect esophageal carcinogenesis has not been elucidated. ADH1B*2 is involved in overproduction of acetaldehyde due to increased ethanol metabolism into acetaldehyde, and ALDH2*2 is involved in accumulation of acetaldehyde due to the deficiency of acetaldehyde metabolism. Acetaldehyde can interact with DNA and form DNA adducts, resulting in DNA damage. N 2 -ethylidene-2′-deoxyguanosine (N 2 -ethylidene-dG) is the most abundant DNA adduct derived from acetaldehyde. Therefore, we quantified N 2 -ethylidene-dG levels in blood samples from 66 Japanese alcoholic patients using liquid chromatography/electrospray tandem mass spectrometry, and investigated the relationship between N 2 -ethylidene-dG levels and ADH1B and ALDH2 genotypes. The median N 2

East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina

“…Figure 2B). These finding were consistent with the well-recognized dominant role of the ALDH2*2 genotype in affecting enzymatic activities [5][6][7]17,18 and indicated that the genotype existed mainly as the heterozygote ALDH2*1/*2 ( Figure 3A and 3B).We therefore combined heterozygote (ALDH2*1/*2) and homozygote (ALDH2*2/*2) as a single category of ALDH2*2 or ALDH2*2 carriers and compared them with the wild homozygote ALDH2*1*1 in the analyses. Figure 4A and 4B).…”

“…17,18 The carriers of ALDH2*2 thus manifest the characteristic of AFS caused by accumulation of ethanol-derived acetaldehyde. [5][6][7] We have shown that CSA is associated with AFS. 9 We and others also reported that CSA was induced by alcohol drinking, particularly in those with AFS.…”

“…[1][2][3][4] East Asians show rapid and intense alcohol flushing after drinking alcohol in an amount that has no effect on whites in up to approximately half of the population. [5][6][7] This is because of the presence of the variant of A B ALDH2 genotype with a substitution of glutamate to lysine at position 504 (Glu504Lys) or ALDH2*2, which is present in East Asians but is virtually absent in other populations of the world. 5-7 ALDH2*2 exerts a dominant-negative effect over wild-type homozygote ALDH2*1*1, and heterozygote ALDH2*1*2 shows severely reduced and homozygote ALDH2*2*2 negligible ALDH2 activity.…”

“…[1][2][3][4] Alcohol (ethanol) flushing syndrome (AFS), including facial flushing, headache, nausea, and palpitation in response to a small amount of alcohol intake, is common among East Asians but is almost absent in other populations of the world. [5][6][7] Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase subunit β (ADH1B) and then to acetic acid by aldehyde dehydrogenase 2 (ALDH2). 8 There are polymorphisms in human ADH1B and ALDH2 genes, and the carriers of variant ADH1B or ADH1B*2 (Arg47His) genotypes have an enhanced enzymatic activity, whereas those of variant ALDH2 or ALDH2*2 (Glu504Lys) genotypes have a severely reduced enzymatic activity.…”

“…8 There are polymorphisms in human ADH1B and ALDH2 genes, and the carriers of variant ADH1B or ADH1B*2 (Arg47His) genotypes have an enhanced enzymatic activity, whereas those of variant ALDH2 or ALDH2*2 (Glu504Lys) genotypes have a severely reduced enzymatic activity. [5][6][7] These genetic variants are commonly found in East Asians (Chinese, Japanese, Koreans, and Taiwanese) but rare or absent in other ethnic populations of the world. [5][6][7] The carriers of these variant genes manifest AFS on intake of small amounts of alcohol because of accumulation of acetaldehyde.…”