Formation of acetaldehyde-derived DNA adducts due to alcohol exposure |
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| Authors: | Hsu-Sheng Yu Tsunehiro Oyama Toyohi Isse Kyoko Kitagawa Thi-Thu-Phuong Pham Masayuki Tanaka Toshihiro Kawamoto |
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| Institution: | 1. Department of Environmental Health, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan;2. Section of Postgraduate Guidance, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan;3. Department of Biochemistry, School of Medicine, Hamamatsu University, 1-20-1 Handayama, Hamamatsu-shi, Shizuoka 431-3192, , Japan;1. VA-Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA;2. Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA;3. Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA;4. Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA;5. The Olson Center for Women''s Health, Department of Obstetrics and Gynecology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA;6. The Center for Environmental Toxicology, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68105, USA;1. School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, Brazil;2. Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil;3. Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba, Canada;4. Centre on Aging, University of Manitoba, Winnipeg, Manitoba, Canada;1. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland;3. Department of Pathology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland;2. Howard Hughes Medical Institute and the Ludwig Center for Cancer Genetics and Therapeutics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland;1. Institute for Genomic Biology, University of Illinois at Urbana-Champaign, 1206 W. Gregory Drive, Urbana, IL 61801, USA;2. Department of Animal Sciences, University of Illinois at Urbana-Champaign, 1207 W. Gregory Drive, Urbana, IL 61801, USA;3. Department of Chemical & Biomolecular Engineering, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, USA;4. Department of Pathobiology, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL 61801, USA;5. Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, 905 S. Goodwin Avenue, Urbana, IL 61801, USA;1. Department of Environmental Science and Analytical Chemistry, Stockholm University, SE-106 91 Stockholm, Sweden;2. Division of Occupational and Environmental Medicine, Institution of Laboratory Medicine, Lund University, SE-221 85 Lund, Sweden;3. Swedish National Food Agency, SE-751 26 Uppsala, Sweden |
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| Abstract: | Epidemiological studies have identified chronic alcohol consumption as a significant risk factor for cancers 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 N2-ethylidene-2′-deoxyguanosine (N2-ethylidene-dG) adduct, which may be converted by reducing agents to N2-ethyl-2′-deoxyguanosine (N2-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 homozygotes. 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 carcinogenesis, 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. |
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