乙醛脱氢酶-2基因及其rs671多态性与相关疾病

乙醛脱氢酶-2(ALDH2)是酒精代谢过程中的关键酶,在酒精代谢产生的高毒性物质乙醛的催化过程中起着重要作用,其基因多态性(尤其是rs671位点多态性)与肝脏疾病、心血管疾病、呼吸道疾病、癌症、阿尔茨海默病(AD)等的发生或发展关系密切,成为近年关注和研究的主要课题。     

人乙醛脱氢酶2基因*1/*2多态性与酒精性疾病

人乙醛脱氢酶2(ALDH2)是乙醇代谢途径中最重要的酶之一,其编码基因aldh2具有高度的多态性.在亚洲的黄种人群中,aldh2*2是频率最高且最重要的突变型.最近的研究显示,aldh2*2能在一定程度上抑制其携带者对酒精的依赖,并与酗酒导致的酒精性中毒、酒精性肝病、上消化道癌及胃癌等疾病之间存在深刻的联系.     

乙醇代谢酶基因多态与肿瘤关系研究进展

致癌物代谢酶基因多态是肿瘤遗传易感性的一个重要方面,体内参与惭醇代谢的酶主要有乙醇脱氢酶（ADH）,乙醛脱氢酶（ALDH）和细胞色素P450－2E1（CYP2E1）,它们均存在基因多态现象,有研究表明,乙醇代谢酶基因多态与肝癌,胃癌和食管癌等肿瘤存在关联,但结果不一致。     

乙醛脱氢酶1与妇科肿瘤关系的研究进展

乙醛脱氢酶1(Acetaldehyde dehydrogenase,ALDH1)是乙醛脱氢酶基因家族的成员之一,在各种不同的组织中广泛存在,参与蛋白质和脂肪等物质的代谢过程,具有氧化活性,可将细胞内的乙醛氧化为乙酸,并降解细胞内的有毒物质。近些年ALDH1作为肿瘤干细胞标志物之一被研究发现,其与多种实体肿瘤的发生、侵袭、转移和预后关系密切,可作为良、恶性肿瘤早期诊断和评估预后的指标之一,有望成为肿瘤基因治疗的新的靶点。本文就乙醛脱氢酶1与妇科肿瘤关系的研究进展做一综述。     

激活ALDH2可减轻心肌缺血的损伤程度

激活线粒体中的乙醛脱氢酶2（ALDH2）可减轻大鼠心肌缺血的损伤程度。这项研究结果刊登于2008年9月12日出版的Science。     

CYP2C19、ALDH2和MTHFR基因多态性与冠心病的相关性研究

目的 探讨细胞色素P450 2C19 (cytochrome P450 2C19,CYP2C19)、乙醛脱氢酶2(acetaldehyde dehydrogenase 2,ALDH2)和亚甲基四氢叶酸还原酶(methylene tetrahydrofolate reductase,MTHFR)基因多态性与冠心病的相关性.方法 分别采用DNA微阵列芯片技术和PCR-芯片杂交方法,对187例冠心病患者和166名健康体检者的CYP2C19、ALDH2和MTHFR位点进行多态性分析.结果 CYP2C19*2/*2、ALDH2 AA和MTHFR TT基因型及频率在冠心病组分别为8.9％、12.3％和34.9％,在对照组分别为3.6％、1.8％和4.1％,两组比较,差异均具有统计学意义(P＜0.05);Logistic回归分析发现ALDH2和MTHFR基因多态性是冠心病发生的重要危险因素,ALDH2 GA和AA基因型:OR值=2.09,MTHFR CT和TT基因型:OR值=2.11.结论 ALDH2和MTHFR基因多态性可增加冠心病的发生风险.     

宁夏回、汉族人群乙醇代谢关键酶ALDH2基因多态性

目的探讨乙醇代谢关键酶乙醛脱氢酶2(ALDH2)基因G1510A位点单核苷酸多态性在宁夏汉族、回族人群中的分布特征。方法应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术对162名回族和236名汉族人群乙醇代谢关键酶ALDH2基因G1510A(rs671位点)多态性位点进行检测。结果宁夏回族群体乙醇代谢关键酶ALDH2基因G1510A位点各基因型频率及等位基因频率分别为GG:69. 14%,GA:27. 16%,AA:3. 70%,G:82. 72%,A:17. 28%。宁夏汉族群体乙醇代谢关键酶ALDH2基因G1510A位点各基因型频率及等位基因频率分别为GG:71. 19%,GA:25. 00%,AA:3. 81%,G:83. 69%,A:16. 31%。按性别分组,乙醇代谢关键酶ALDH2基因G1510A位点的基因型频率及等位基因频率亦无差异。结论乙醇代谢关键酶ALDH2基因G1510A位点在宁夏回、汉族人群中的分布无明显差异。     

乙醛脱氢酶2在大鼠心肌缺氧损伤中的抗凋亡作用

目的： 检测大鼠心肌在缺氧条件下发生细胞凋亡的变化，以及乙醛脱氢酶2（ALDH2）在此过程中所起的作用。 方法： 运用缺氧模型，比较大鼠心肌细胞在单独缺氧和经ALDH2特异性抑制剂daidzin预处理24 h后缺氧的凋亡改变，酶活性检测采用乙醛代谢法、凋亡的测定通过用Hoechest 33324、免疫荧光标记用流式细胞仪测定和TUNEL试剂盒检测。 结果： 心肌细胞在daidzin作用下，其酶活性被抑制而细胞无凋亡发生。在daidzin预处理24 h后再经缺氧诱导，比单独缺氧引起的心肌细胞凋亡更为明显：表现为在Hoechest 33324染色中，细胞核溶解和核碎裂(P<0.05)，FACS和TUNEL显示，凋亡细胞明显增加(P<0.05)。 结论： ALDH2酶活性降低可增加心肌细胞对缺氧导致凋亡的易感性，ALDH2对缺氧引起的细胞凋亡有拮抗作用。     

微小RNA-423-5p靶向乙醛脱氢酶2减轻脂多糖诱导的人脐静脉血管内皮细胞损伤

目的 探讨微小RNA-423-5p(miR-423-5p)对脂多糖（LPS）诱导血管内皮细胞损伤的保护及作用机制。方法 用1 mg/L LPS诱导人脐静脉血管内皮细胞（HUVECs）24 h,Real-time PCR和Western blotting检测细胞中miR-423-5p和乙醛脱氢酶2（ALDH2）的表达。通过转染anti-miR-423-5p和pcDNA-ALDH2下调miR-423-5p和上调ALDH2表达,流式细胞术检测细胞凋亡率,Western blotting检测凋亡相关蛋白Bcl-2和Bax的表达,并用ELISA试剂盒检测LPS诱导后细胞上清液中白细胞介素6（IL-6）和肿瘤坏死因子α（TNF-α）的含量;双荧光素酶报告系统验证miR-423-5p与ALDH2的调控关系。结果 与对照相比,LPS可诱导HUVECs凋亡和损伤,使HUVECs中miR-423-5p、Bax表达量及IL-6和TNF-α分泌量均显著升高（P<0.05）,ALDH2的mRNA和蛋白表达量及Bcl-2量显著降低（P<0.05）;下调mi-423-5p表达和过表达ALDH2均可减轻LPS诱导的HUVECs损伤并抑制细胞凋亡;miR-423-5p靶向负调控ALDH2的表达;抑制ALDH2表达逆转了下调miR-423-5p表达对LPS诱导的HUVECs损伤的作用。结论 下调miR-423-5p表达可靶向ALDH2减轻LPS对HUVECs的损伤并抑制细胞凋亡。     

广州市番禺地区体检人群ALDH2基因的多态性分析

目的研究广州市番禺地区体检人群乙醛脱氢酶2(ALDH2)基因的多态性分布。方法选取2017年1月至2018年3月在广州市番禺区中心医院进行ALDH2基因多态性检测的体检人群712例。采用基因芯片法进行ALDH2 基因rs671位点多态性检测,并与已报道的我国其他地区人群的ALDH2 基因多态性结果进行比较。结果本地区体检人群ALDH2 基因rs671位点检测结果分为三种基因型:GG型、GA型和AA型,其频率分别为64.04%、31.74%和4.22%。本地区与四川、上海和武汉地区比较,ALDH2基因型差异无统计学意义(P0.05),与北京、山东和台湾地区比较差异有统计学意义(P0.05)。结论广州市番禺地区ALDH2基因多态性分布具有一定的地域特性,对指导健康饮酒以及硝酸甘油的合理用药上都有重要意义。     

Genetic polymorphisms of alcohol metabolizing enzymes.

Alcohol metabolism is one of the biological determinants that can significantly influence drinking behavior and the development of alcoholism and alcohol-induced organ damage. Most ethanol elimination occurs by oxidation to acetaldehyde and acetate, catalyzed principally by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Other ethanol oxidation pathways, including catalase and microsomal ethanol-oxidizing system (MEOS/CYP2E1), as well as the nonoxidative pathway (FAEES), which forms fatty acid ethyl esters, appear to play a minor role. The major alcohol metabolizing enzymes exhibit genetic polymorphism and ethnic variation. In this review recent advances in the understanding of the functional polymorphisms of ADH, ALDH and CYP2E1 and their metabolic, physiologic and clinical correlations are presented.     

Cytosolic aldehyde dehydrogenase (ALDH1) variants found in alcohol flushers

Although mitochondrial aldehyde dehydrogenase (ALDH2) has been thought to play a major role in acetaldehyde detoxification, and the high incidence of 'alcohol flushing' among Orientals is attributed to the inherited deficiency of ALDH2, the role of cytosolic aldehyde dehydrogenase (ALDH1) cannot be ignored. On the premise that alcohol flushing in Caucasians could be related to ALDH1 abnormalities, we examined the enzyme properties and electrophoretic mobilities of ALDH1 partially purified from red blood cells of nine unrelated alcohol flushers. One exhibited very low activity (10–20% of control level), and another exhibited moderately low activity (60%) and altered kinetic properties. The electrophoretic mobilities of these two samples were also distinguishable from the control samples. Immunological quantitation indicated that the amounts of ALDH1 protein in these two samples were not reduced in parallel with their enzyme deficiency. In the first case, the two characteristics, i.e. very low enzyme activity and alcohol flushing, were inherited by her daughter.     

Mendelian randomization: a novel test of the gateway hypothesis and models of gene-environment interplay

To determine if drinking behavior in adolescence provides a "gateway" leading to the misuse of other psychoactive substances and antisocial behavior, we genotyped 180 Asian adolescent adoptees to determine if they inherited the deficient from of the aldehyde dehydrogenase 2 (ALDH2) enzyme that is important in the metabolism of alcohol. Based on the gateway model, we hypothesized that those with normal enzyme activity (70% of the sample) who began to misuse alcohol would also misuse other drugs and display antisocial tendencies. Those with the enzyme deficiency (30%), because they experience unpleasant side effects associated with drinking, were expected to show less evidence of alcohol misuse and thus be less likely to progress to the misuse of other substances or engage in antisocial acts. Consistent with previous research, we found that ALDH2 deficiency was significantly associated with lower rates of drinking and getting drunk but not with ever having tried alcohol. Contrary to the gateway model, we found no evidence that ALDH2 deficiency was associated with lower rates of nonalcohol substance use or antisociality. Finally, in an examination of factors that may moderate the impact of the metabolic protection because of ALDH2 deficiency, we identified siblings rather than parents as the major source of familial environmental effect on adolescent drinking.     

Genotypes of aldehyde dehydrogenase and alcohol dehydrogenase polymorphisms in patients with leber’s hereditary optic neuropathy

Summary To define whether alcohol drinking provides a risk for Leber’s hereditary optic neuropathy (LHON), the genotypes of lowK _m aldehyde dehydrogenase (ALDH2) and alcohol dehydrogenase type 2 (ADH₂), major enzymes involving the alcohol metabolism, were examined in 29 unrelated Japanese patients with LHON associated with mitochondrial DNA 11778 mutation, 24 unrelated asymptomatic carriers with the mutation and 57 normal controls without the mutation. PCR-restriction detection revealed three genotypes of ALDH2 and ADH₂. The allele frequencies of either enzyme in LHON patients, asymptomatic carriers, or both, did not differ from those in normal controls. There is no association between LHON and genotypes of alcohol-metabolizing enzymes. However, six of the LHON patients had frequent alcohol consumption, while none of the asymptomatic carriers claimed frequent drinking habit. Thus, we could not make a denial of drinking effects on optic nerve damage in LHON.     

Refined Geographic Distribution of the Oriental ALDH2*504Lys (nee 487Lys) Variant

Mitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2*504Lys variant functions as a dominant negative, greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2*504Lys , we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2*504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2*504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2*504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2*504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2*504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures.     

Alcohol metabolizing enzymes: Studies of isozymes in human biopsies and cultured fibroblasts

Rapid and sensitive micromethods for the study of alcohol dehydrogenase and adehyde dehydrogenase isozymes in skin extracts, cultured fibroblasts and other organs are presented. Possibilities for the application of these techniques to the study of interindividual variations in response to alcohol are discussed. While fibroblasts cultured from a skin biopsy from one Japanese individual revealed a heterodimer (ADH2 2-1) of alcohol dehydrogenase, skin extract from another Japanese showed a homodimer (ADH2 2-2). Up to four isozyme sets for aldehyde dehydrogenase (ALDH) were detected in various human organs and at least three sets were found in skin and fibroblasts extracts. Our preliminary data on liver, stomach, and skin indicate that ALDH is polymorphic and several loci are concerned in the determination of these isozyme sets.     

Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism

The alcohol-flush reaction occurs in Asians who inherit the mutantALDH2 ^*2 allele that produces an inactive aldehyde dehydrogenase enzyme. In these individuals, high blood acetaldehyde levels are believed to be the cause of the unpleasant symptoms that follow drinking. We measured the alcohol elimination rates and intensity of flushing in Chinese subjects in whom the alcohol dehydrogenaseADH2 andALDH2 genotypes were determined. We also correlatedADH2, ADH3, andALDH2 genotypes with drinking behavior in 100 Chinese men. We discovered thatADH2 ^*2 andADH3 ^*1, alleles that encode the high activity forms of alcohol dehydrogenase, as well as the mutantALDH2 ^*2 allele were less frequent in alcoholics than in controls. The presence ofALDH2 ^*2 was associated with slower alcohol metabolism and the most intense flushing. In those homozygous forALDH2 ^*1, the presence of twoADH2 ^*2 alleles correlated with slightly faster alcohol metabolism and more intense flushing, although a great deal of variability in the latter was noted.     

Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population.

Alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P-4502E1 (CYP2E1), and then to acetate by aldehyde dehydrogenase (ALDH). Polymorphisms of these ethanol-metabolizing enzymes may be associated with inter-individual difference in alcohol metabolism and susceptibility to alcoholic liver disease. We determined genotype and allele frequencies of ALDH2, CYP2E1, ADH2, and ADH3 in male Korean patients with alcoholic cirrhosis (n=56), alcoholics without evidence of liver disease (n=52), and nondrinkers (n=64) by using PCR or PCR-directed mutagenesis followed by restriction enzyme digestion. The prevalences of heterozygous ALDH2*1/*2 plus homozygous ALDH2*2/*2 in patients with alcoholic cirrhosis (7.1%) and alcoholics without evidence of liver disease (3.8%) were significantly lower than that in nondrinkers (45.3%). The c2 allele frequencies of the CYP2E1 in alcoholic cirrhosis, alcoholics without evidence of liver disease, and nondrinkers were 0.21, 0.20, and 0.20, respectively. Allele frequencies of ADH2*2 in the three groups were 0.78, 0.74, and 0.77 and those of ADH3*1 were 0.94, 0.98, and 0.95. Therefore, we confirmed the observation that the ALDH2*2 gene protects against the development of alcoholism. However, the development of cirrhosis in Korean alcoholic patients was not associated with polymorphisms of ethanol-metabolizing enzymes.