Chemico-Biological Interactions 188 (2010) 367–375 Contents lists available at ScienceDirect Chemico-Biological Interactions j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h e m b i o i n t Mini-review Formation of acetaldehyde-derived DNA adducts due to alcohol exposure Hsu-Sheng Yu a,∗ , Tsunehiro Oyama a , Toyohi Isse b , Kyoko Kitagawa c , Thi-Thu-Phuong Pham a , Masayuki Tanaka a , Toshihiro Kawamoto a a Department of Environmental Health, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan b Section of Postgraduate Guidance, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan c Department of Biochemistry, School of Medicine, Hamamatsu University, 1-20-1 Handayama, Hamamatsu-shi, Shizuoka 431-3192, , Japan a r t i c l e i n f o Article history: Received 7 May 2010 Received in revised form 18 August 2010 Accepted 25 August 2010 Available online 21 September 2010 Keywords: Acetaldehyde ALDH2 DNA adducts Ethanol metabolism N 2 -ethyl-dG a b s t r a c t Epidemiological studies have identified chronic alcohol consumption as a significant risk factor for can- cers of the upper aerodigestive tract, including the oral cavity, pharynx, larynx and esophagus, and for cancer of the liver.Ingested ethanol is mainly oxidized by the enzymes alcohol dehydrogenase (ADH), cytochrome P-450 2E1 (CYP2E1),and catalase to form acetaldehyde, which is subsequently oxidized by aldehyde dehydrogenase 2 (ALDH2) to produce acetate. Polymorphisms of the genes which encode enzymes for ethanol metabolism affect the ethanol/acetaldehyde oxidizing capacity. ADH1B*2 allele (ADH1B, one of the enzyme in ADH family) is commonly observed in Asian population, has much higher enzymatic activity than ADH1B*1 allele. Otherwise, approximately 40% of Japanese have single nucleotide polymorphisms (SNPs) of the ALDH2 gene. The ALDH2 *2 allele encodes a protein with an amino acid change from glutamate to lysine (derived from the ALDH2*1 allele) and devoid of enzymatic activity. Neither the homozygote (ALDH2*2/*2) nor heterozygote (ALDH2*1/*2) is able to metabolize acetaldehyde promptly. Acetaldehyde is a genotoxic compound that reacts with DNA to form primarily a Schiff base N 2 - ethylidene-2 ′ -deoxyguanosine (N 2 -ethylidene-dG) adduct, which may be converted by reducing agents to N 2 -ethyl-2 ′ -deoxyguanosine (N 2 -ethyl-dG) in vivo,and strongly blocked translesion DNA synthesis. Several studies have demonstrated a relationship between ALDH2 genotypes and the development of certain types of cancer.On the other hand,the drinking of alcohol induces the expression of CYP2E1, resulting in an increase in reactive oxygen species (ROS) and oxidative DNA damage. This review covers the combined effects of alcohol and ALDH2 polymorphisms on cancer risk. Studies show that ALDH2*1/*2 heterozygotes who habitually consume alcohol have higher rates of cancer than ALDH2*1/*1 homozy- gotes.Moreover, they support that chronic alcohol consumption contributes to formation of various DNA adducts. Although some DNA adducts formation is demonstrated to be an initiation step of carcino- genesis, it is still unclear that whether these alcohol-related DNA adducts are true factors or initiators of cancer. Future studies are needed to better characterize and to validate the roles of these DNA adducts in human study. © 2010 Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 2. ADH polymorphisms and metabolism of ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 3. ALDH2 polymorphisms and alcohol-related carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368 4. Carcinogenicity of acetaldehyde . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369 Abbreviations: AA, acetaldehyde; ADH, alcohol dehydrogenase; ALDH2, aldehyde dehydrogenase 2; CBI, covalent binding index; CRA, crotonaldehyde; CYP2E1, cytochrome P-450 2E1; dA, deoxyadenosine; dC, deoxycytidine; dG, deoxyguanosine; 4-HNE, 4-hydroxy-2-nonenal; HPLC-ECD, high performance liquid chromatography-electrochemical detector; IARC, International Agency for Research on Cancer; ICLs, interstrand cross links; MAA, malondialdehyde- acetaldehyde; MDA, malondialdehyde; ␣-Me-␥-OH-PdG, ␣-methyl-␥-hydroxy-1,N 2 -propanodeoxyguanosine; M1G, pyrimido-[1,2-a]purin-10(3H)-one; N 2 -Dio-dG, N 2 -(2,6-dimethyl-1,3-dioxan-4-yl)-deoxyguanosine; N 2 -ethyl-dG, N 2 -ethyl-2 ′ -deoxyguanosine; N 2 -ethylidene-dG, N 2 -ethylidene-2 ′ -deoxyguanosine; N 6 -HOMe-dA, N 6 - hydroxymethyl-deoxyadenosine; 8-OH-dG, 8-hydroxy-2 ′ -deoxyguanosine; ROS, reactive oxygen species; SNP, single nucleotide polymorphism. ∗ Corresponding author. Tel.: +81 93 691 7429; fax: +81 93 691 9341. E-mail address: yu@med.uoeh-u.ac.jp (H.-S. Yu). 0009-2797/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2010.08.005