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

Cancer Sci. 2012 Sep;103(9):1651-5. doi: 10.1111/j.1349-7006.2012.02360.x. Epub 2012 Jul 24.


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)-ethylidene-dG levels (25th percentile, 75th percentile) in patients with ADH1B*1/*1 plus ALDH2*1/*1, ADH1B*2 carrier plus ALDH2*1/*1, ADH1B*1/*1 plus ALDH2*1/*2, and ADH1B*2 carrier plus ALDH2*1/*2 were 2.14 (0.97, 2.37)/10(7) bases, 2.38 (1.18, 2.98)/10(7) bases, 5.38 (3.19, 6.52)/10(7) bases, and 21.04 (12.75, 34.80)/10(7) bases, respectively. In the ALDH2*1/*2 group, N(2)-ethylidene-dG levels were significantly higher in ADH1B*2 carriers than in the ADH1B*1/*1 group (P < 0.01). N(2)-ethylidene-dG levels were significantly higher in the ALDH2*1/*2 group than in the ALDH2*1/*1 group, regardless of ADH1B genotype (ADH1B*1/*1, P < 0.05; ADH1B*2 carriers, P < 0.01) N(2)-ethylidene-dG levels in blood DNA of the alcoholics was remarkably higher in individuals with a combination of the ADH1B*2 and ALDH2*2 alleles. These results provide a new perspective on the carcinogenicity of the acetaldehyde associated with alcoholic beverages, from the aspect of DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaldehyde / metabolism*
  • Adult
  • Alcohol Dehydrogenase / genetics*
  • Alcoholism / genetics*
  • Alcoholism / metabolism*
  • Aldehyde Dehydrogenase / genetics*
  • Aldehyde Dehydrogenase, Mitochondrial
  • Alleles
  • Asian People
  • DNA Adducts / blood
  • DNA Adducts / chemistry
  • DNA Damage*
  • Deoxyguanosine / analogs & derivatives
  • Deoxyguanosine / blood
  • Deoxyguanosine / chemistry
  • Genotype
  • Humans
  • Japan
  • Middle Aged
  • Polymorphism, Single Nucleotide*


  • DNA Adducts
  • N2-ethylidene-2'-deoxyguanosine
  • ADH1B protein, human
  • Alcohol Dehydrogenase
  • ALDH2 protein, human
  • Aldehyde Dehydrogenase
  • Aldehyde Dehydrogenase, Mitochondrial
  • Deoxyguanosine
  • Acetaldehyde