Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms
Genotoxic effects of alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms
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DOI：
10.1016/j.mrfmmm.2006.11.026
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发表时间：
2007-02-03
影响因子：
2.3
通讯作者：
Yokoyama, Kazuhito
中科院分区：
文献类型：
--
作者：
Ishikawa, Hitoshi;Ishikawa, Takashi;Yokoyama, Kazuhito
乙醇在体内几乎完全被氧化代谢分解。乙醇本身被认为既不致癌，也不致突变，也不具有遗传毒性。然而，在乙醇转化为乙醛和醋酸盐的代谢过程中，生物体同时暴露于乙醇和乙醛中，因此乙醇被怀疑是共致癌物质。乙醇脱氢酶-2 （ADH1B）和乙醛脱氢酶-2 （ALDH2）的遗传多态性影响酒精的代谢。ADHIB*1/*1基因型编码低活性形式的ADH1B， ALDH2*1/*2和ALDH2*2/*2基因型编码无活性的ALDH2。本研究的目的是验证ADHIB和ALDH2基因多态性与饮酒引起的遗传毒性显著相关的假设，使用细胞分裂阻断微核（CBMN）测定286名健康日本男性外周血淋巴细胞，这是一种已建立的基因组不稳定性生物标志物。习惯饮酒者和无吸烟习惯的中度饮酒者的平均微核（MN）频率随ADH1B *1等位基因数量的增加而增加（P=0.039或P=0.029），随ALDH2 *2等位基因数量的增加而增加（P=0.019或P=0.037）。logistic回归分析显示，当ADH1B* 2/*2基因型受试者的OR定义为1.00时，ADH1B*1等位基因的受试者中MN频率水平高于MN中位数（3.0）的受试者数量显著高于调整后的估计（OR 2.08, 95% ci 1.24-3.48）。当ALDH2*1/*1基因型受试者的OR定义为1.00时，携带ALDH2*2等位基因的受试者中MN频率水平高于MN中位数的受试者数量也显著增加（OR为1.79,95% ci为1.04-3.11）。这项研究的结果已经确定了ADH1B/ALDH2多态性与酒精饮用者遗传毒性之间重要的新关联。(c) 2006 Elsevier B.V.版权所有
Ethanol is almost totally broken down by oxidative metabolism in vivo. Ethanol per se is considered to be neither carcinogenic, mutagenic nor genotoxic. However, during the metabolic conversion of ethanol to acetaldehyde and acetate, the organism is exposed to both ethanol and acetaldehyde and therefore ethanol is suspected to be co-carcinogenic. The genetic polymorphisms of alcohol dehydrogenase-2 (ADH1B) and acetaldehyde dehydrogenase-2 (ALDH2) influence the metabolism of alcohol. The ADHIB*1/*1 genotype encodes the low-activity form of ADH1B, and ALDH2*1/*2 and ALDH2*2/*2 genotype encode inactive ALDH2. The aim of this study was to test the hypothesis that polymorphisms of the ADHIB and ALDH2 genes are significantly associated with genotoxicity induced by alcohol drinking, measured using the cytokinesis-block micronucleus (CBMN) assay, an established biornarker of genome instability, in peripheral blood lymphocytes of 286 healthy Japanese men. There was a significant trend for the mean micronuclei (MN) frequency in habitual or moderate drinkers without a smoking habit to increase as the numbers of the *1 allele in ADH1B increased (P=0.039 or P=0.029) and the *2 allele in ALDH2 increased (P=0.019 or P=0.037). A logistic regression analysis showed that the number of subjects with MN frequency levels more than median value of MN (3.0) was significantly higher in the subjects with the ADH1B*1 allele as adjusted estimates (OR 2.08, 95% C.I. 1.24-3.48), when the OR for the subjects with the ADHIB*2/*2 genotype was defined as 1.00. The number of subjects with MN frequency levels more than median value of MN was also significantly higher in the subjects with the ALDH2*2 allele as adjusted estimates (OR 1.79, 95% C.I. 1.04-3.11), when the OR for the subjects with the ALDH2*1/*1 genotype was defined as 1.00. The results of this study have identified important novel associations between ADH1B/ALDH2 polymorphisms and genotoxicity in alcohol drinkers. (c) 2006 Elsevier B.V. All rights reserved.