Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
Chem Biol Interact. 2010 Dec 5;188(3):367-75. doi: 10.1016/j.cbi.2010.08.005. Epub 2010 Sep 21.
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. ADH1B2 allele (ADH1B, one of the enzyme in ADH family) is commonly observed in Asian population, has much higher enzymatic activity than ADH1B1 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 ALDH21 allele) and devoid of enzymatic activity. Neither the homozygote (ALDH2*2/2) nor heterozygote (ALDH21/2) 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 ALDH21/2 heterozygotes who habitually consume alcohol have higher rates of cancer than ALDH21/*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.
流行病学研究已经确定慢性酒精摄入是上呼吸道癌，包括口腔、咽、喉和食管，以及肝癌的重要危险因素。摄入的乙醇主要通过醇脱氢酶（ADH）、细胞色素 P-450 2E1（CYP2E1）和过氧化氢酶氧化为乙醛，随后乙醛脱氢酶 2（ALDH2）将其氧化为乙酸。编码乙醇代谢酶的基因多态性影响乙醇/乙醛氧化能力。ADH1B2 等位基因（ADH1B，ADH 家族中的一种酶）在亚洲人群中很常见，其酶活性比 ADH1B1 等位基因高得多。另一方面，大约 40%的日本人存在乙醛脱氢酶 2 基因的单核苷酸多态性（SNP）。ALDH22 等位基因编码一种氨基酸从谷氨酸变为赖氨酸的蛋白质（源自 ALDH21 等位基因），并且没有酶活性。无论是纯合子（ALDH2*2/2）还是杂合子（ALDH21/2）都不能迅速代谢乙醛。乙醛是一种遗传毒性化合物，与 DNA 反应形成主要的席夫碱 N(2)-乙基-2'-脱氧鸟苷（N(2)-乙基-2'-脱氧鸟苷）加合物，该加合物在体内可被还原剂转化为 N(2)-乙基-2'-脱氧鸟苷（N(2)-乙基-2'-脱氧鸟苷），并强烈阻止跨损伤 DNA 合成。几项研究表明，ALDH2 基因型与某些类型癌症的发展之间存在关系。另一方面，饮酒会诱导 CYP2E1 的表达，导致活性氧（ROS）和氧化 DNA 损伤增加。这篇综述涵盖了酒精和 ALDH2 多态性对癌症风险的综合影响。研究表明，习惯性饮酒的 ALDH21/2 杂合子比 ALDH21/*1 纯合子患癌症的比率更高。此外，他们还支持慢性酒精摄入有助于形成各种 DNA 加合物。虽然已经证明一些 DNA 加合物的形成是致癌作用的起始步骤，但尚不清楚这些与酒精相关的 DNA 加合物是否是癌症的真正因素或启动子。需要进一步的研究来更好地描述和验证这些 DNA 加合物在人类研究中的作用。
