细胞色素P450-2E1基因型对2-乙氧基乙醇代谢影响的研究

目的 探讨细胞色素P450－2E1（CYP2E1）不同基因型代谢2－乙氧基乙醇（EE）能力是否存在差异。方法 采用个体采样,毛细柱气相色谱分析技术及聚合酶链反应（PCR）检测方法,比较不同基因型个体累计接触EE剂量与2－乙在线性关系,B、C基因型回归系数大于A基因型。结论 CYP2E1B、C基因型代谢EE能力强于A基因型。     

2-乙氧基乙醇生物学检测研究进展

２－乙氧基乙醇（ＥＥ）广泛应用于激光照排等高技术产业,接触ＥＥ人数正逐渐增加,其职业危害日益受到关注。对接触者进行生物检测可以预测ＥＥ对机体的损害,评价其危险度,从而提出可行的干预措施,保护工人健康。现将ＥＥ重托检测进展作一概述。     

2-乙氧基乙醇染毒对大鼠某些脂质过氧化相关指标的影响

目的：观察2－乙氧基乙醇（EE）染毒大鼠与脂质过氧化过程有关的某些生化指标的变化,并探讨EE染毒是否诱发血清脂质过氧化（LPO）升高及其可能机理。方法：选取雄性Wistar大鼠,随机分为4组：对照组、EE分别为200、400、800mg/kg组,每组30只。每天染毒1次,每周6次,持续6周。分别于染毒每周后,将各组动物随机处死5只,对血液及肝脏中的脂质过氧化相关指标进行测定。结果：血清LPO水平显著升高;血清铜蓝蛋白（CP）、血清超氧化物歧化酶（SOD）和肝脏SOD活性显著升高;肝脏过氧化氢酶（CAT）活性显著下降,肝脏GSH－Px活性变化不明显。结论：EE长期染毒可诱发大鼠LPO水平升高,这可能是EE诱发大量活性氧（ROS）产生和影响大鼠抗氧化机制共同作用的结果。     

2—乙氧基乙醇对小鼠肝脏损伤的研究

目的：探讨2－乙氧基乙醇对肝脏的损伤机制。方法：对小鼠进行2－乙氧基乙醇腹腔注射亚慢性染毒并观察小鼠肝脏生化代谢的改变。结果：肝脏一氧化氮含量,一氧化氮合成酶活性自第1周开始比对照组明显增加（P＜0．05）,二者实验组第2,3,4周均比第1周实验组显著增加（P＜0．01）,超氧化物歧化酶活性自第3周开始比对照组和第1周实验组显著增强（P＜0．01）,脂质过氧化产物丙二醛含量自第2周开始比对照组和第1周实验组显著增加（P＜0．01）,上述指标呈良好时间－效应关系,染毒组血清谷丙转氨酶活性自第1周起比对照组显著升高（P＜0．05）,第4周回落。结论：2－乙氧基乙醇能引起肝脏一氧化氮自由基增加并诱发脂质过氧化反应对肝脏发生毒性作用。     

2-乙氧基乙醇毒理学及卫生标准研究进展

职业流行病学调查和动物毒理学实验表明,２－乙氧基乙醇（ＥＥ）可引起生殖发育毒性、血液毒性和神经毒性。其毒代动力学特征表现为经呼吸道、皮肝同时吸收,且以后者为主,半衰期较长。ＥＥ的主要代谢产物为２－乙氧基乙酸（ＥＡＡ）,是导致生殖／发育毒笥的最终物质。ＥＥ的化学结构与甘氨酸类似,可选择性地竞争一碳单位合成,干扰了代谢旺盛的细胞组织系统,如性腺、血液、骨髓和神经等。本综述为我国开展安全性评价及健康危险     

接触2-乙氧基乙醇对LDH-C4活性影响与精子毒性的关系

为研究ＥＥ精子毒性及生物效应标志物，对ＰＳ版作业男工ＬＤＨ－Ｃ４活性／精子毒性进行调查，同时对小鼠附睾组织匀浆ＬＤＨ－Ｃ４活性测定。结果表明接触ＥＥ在７７ｍｇ／ｍ３以上男工精液ＬＤＨ－Ｃ４活性受到抑制。随着接触水平增加，ＬＤＨ－Ｃ４活性下降越明显，呈明显的剂量－反应关系。在２４３ｍｇ／ｋｇ剂量以上，小鼠ＬＤＨ－Ｃ４活性也显著下降，亦有相同的规律，提示ＬＤＨ－Ｃ４活性降低可以作为精子毒效应评价指标。     

毛细柱气相色谱法检测尿中2—乙氧基乙酸

2-乙氧基乙醇(2-ethoxyethanol EE)是工业与民用产品生产中广泛使用的有机溶剂,它可经呼吸道、皮肤进入人体内。2-乙氧基乙酸(2-ethoxyacetic acid EAA)是EE在体内的主要代谢产物,由尿排出。气相色谱法检测尿中EAA,国外已有报道,而国内尚未见这方面研究。本文利用毛细柱气相色谱法-氢焰离子化检测器建立一种测定尿中EAA的分析方法。该法灵敏、迅速、准确,为EE接触工人的健康监护提供了方法和依据。     

2-乙氧基乙醇急性染毒大鼠血清和睾丸某些抗氧化指标的变化

目的 观察2-乙氧基乙醇(2-Ethoxythanol,EE)急性染毒对SD大鼠血清和睾丸某些抗氧化指标的变化，探讨EE致睾丸损伤的可能机制。方法 选择健康雄性SD大鼠，体重180-220g。随机分为对照组、EE800、1600和3200mg／kg组4组，每组24只。采取一次性灌胃染毒。于灌胃后12、24、48和72h，将各组动物随机处死6只，留取动物血液、睾丸，制备血清和睾丸匀浆，测定血清和睾丸匀浆脂质过氧化物(LPO)水平、超氧化物歧化酶(SOD)活性、过氧化氢酶(CAT)活性，以及血清铜蓝蛋白(CP)活性。结果 与对照组比较，各染毒组睾／体比明显下降(P＜0.05)，睾丸匀浆LPO水平和血清CP活性增高。染毒12、24h，血清CAT、睾丸匀浆CAT和SOD活性增高，而染毒48、72h后，血清CAT、睾丸匀浆CAT和SOD活性显著降低(P＜0.05)。EE各染毒组血清LPO水平和SOD活性变化不明显。结论 推测EE毒作用的靶器官可能是睾丸，睾丸抗氧化功能的改变是EE致睾丸毒性的可能机制。     

2—乙氧基乙醇作业工人的血清甘油三酯和胆固醇水平变化

对北京市甲、乙两个印刷材料厂ＥＥ作业工人劳动卫生学调查结果发现，甲厂ＰＳ版涂布工序和乙厂ＰＳ版涂布及ＰＳ烘干工序空气中ＥＥ浓度均超过美国ＴＬＶ－ＴＷＡ１９ｍｇ／ｍ３标准。ＥＥ作业工人血清胆固醇含量极显著高于对照组（Ｐ＜０．００１），而甘油三酯含量极显著低于对照组（Ｐ＜０．００１）。表明ＥＥ对接触者脂代谢有影响。     

Biochemical genetic analysis of human and rodent aldehyde dehydrogenase (ALDH)

ALDH isozymes have been characterized in terms of substrate and coenzyme specificity, heat stability, tissue distribution and electrophoretic properties. The activity of the isozymes has also been examined in rodent-human somatic cell hybrids in order to map the structural genes to specific chromosomes and to study the control of gene expression. One isozyme, designated ALDH3, which is very active against benzaldehyde, was found to show variable expression in hybrids made between rat hepatoma cells and human fibroblasts or fetal liver. Segregation analysis of these hybrids indicates that the structural locus for human ALDH3 may be on chromosome 17. The expression of rodent ALDH3 in these hybrids was extremely variable and not correlated with the appearance of the human enzyme. In hybrids expressing human and rodent ALDH3 no heteromeric isozymes were observed. The human "cytosolic" ALDH1 and "mitochondrial" ALDH2 isozymes did not appear to be expressed in any of the somatic cell hybrids examined.     

酒精代谢酶基因型在日本双生子中的分布

目的为预防酒精相关性疾病发生,调查了酒精代谢酶控制基因在日本双生子中的分布。方法以饱和酚法提取ＤＮＡ,应用限制性片段长度多态性分析技术检测了９２个日本双生子的酒精脱氢酶２（ＡＤＨ２）和乙醛脱氢酶２（ＡＬＤＨ２）基因型,根据基因型差异筛选敏感个体。结果ＡＤＨ２和ＡＬＤＨ２基因分布符合Ｈａｒｄｙｗｅｉｎｂｅｒｇ等式。ＡＤＨ２基因的３种基因型分别是ＡＤＨ２１／ＡＤＨ２１（１．１％）、ＡＤＨ２１／ＡＤＨ２２（４４．６％）和ＡＤＨ２２／ＡＤＨ２２（５４．３％）。ＡＬＤＨ２的基因型分别为ＡＬＤＨ２１／ＡＬＤＨ２１（４１．３％）、ＡＬＤＨ２１／ＡＬＤＨ２２（３９．１％）和ＡＬＤＨ２２／ＡＬＤＨ２２（１９６％）。ＡＤＨ２和ＡＬＤＨ２基因频率分别为０．２５５、０．７４５和０６０９、０３９１。结论异常纯合的ＡＤＨ２基因和纯合的ＡＬＤＨ２基因占优势。个体携有ＡＤＨ２１／ＡＤＨ２２和ＡＬＤＨ２１／ＡＬＤＨ２１、ＡＤＨ２２／ＡＤＨ２２和ＡＬＤＨ２１／ＡＬＤＨ２１者可视为敏感个体。     

Ethanol feeding can produce secondary alterations in aldehyde dehydrogenase isozymes

Depressed hepatic aldehyde dehydrogenase (ALDH) activity levels have been observed in alcoholics, but whether the deficit is primary or secondary in nature remains controversial. In this study, we examined liver ALDH in rodent (rat) and primate (baboon) animal models pair-fed nutritionally adequate ethanol or isocaloric carbohydrate containing liquid diets. Both species show qualitative changes in ALDH isozymes after ethanol consumption. The changes include alterations in isozyme patterns seen upon electrofocusing and decreased responsiveness to the ALDH inhibitor, disulfiram. The subcellular locus of most of the changes is cytosolic in the baboon and mitochondrial in the rat. Study of partially purified (enriched) baboon cytosolic ALDH confirmed changes seen in the original cytosols and kinetic characterization of the enriched enzyme revealed a 9-fold higher Km for acetaldehyde in ALDH from an ethanol treated animal. We note that qualitative and quantitative changes secondary to ethanol treatment in the primate model closely parallel those described in human alcoholics.     

乙醛脱氢酶2基因多态性及环境暴露与胃癌易感性

目的探讨乙醛脱氢酶2（ALDH2）基因多态性及环境暴露与胃癌易感性的关系。方法采用1：1配对病例一对照研究和扩增产物长度多态性（APLP）方法，检测南京市169例原发性胃癌患者和对照的ALDH2基因型，分析其在胃癌发生中的作用；结合环境危险因素分析，对ALDH2基因多态性与环境危险因素在胃癌发生中的交互作用进行分析。结果ALDH2基因型在病例组和对照组分布差异有统计学意义（X^2=4．617，P=0．032）。消化道疾病史、腌制食品、三餐不定时、暴饮暴食4项因素与胃癌发生的危险性增加有关；ALDH2基因与消化道疾病史、三餐不定时及暴饮暴食存在一定的交互作用。结论ALDH2基因多态性与胃癌易感性有关，并与环境暴露有一定的交互作用。关键词：乙醛脱氢酶2（ALDH2）基因；基因多态性；胃癌；易感性     

利用限制性片段长度多态性分析检测乙醛脱氢酶基因2的基因型

人类摄入酒精主要通过Ⅰ型酒精脱氢酶和乙醛脱氢酶共同催化。为建立乙醛脱氢酶基因２（ＡＬＤＨ２）的基因型检测方法，本研究应用限制性片段长度多态性分析法（ＲＦＬＰ－ＰＣＲ）测定ＡＬＤＨ２的基因型。根据ＡＬＤＨ２的基因序理资料，设计一含一个碱基替代的限制性内切酶ＭｂｏⅡ的可识别位点。随后ＤＮＡ模板在下列条件扩增；变性；９４，１ｍｉｎ，退火；５７℃，３ｍｉｎ，延伸；７２℃１ｍｉｎ。３５个循环。聚合酶链反应产     

Relationships of alcohol dehydrogenase 1B (<Emphasis Type="Italic">ADH1B</Emphasis>) and aldehyde dehydrogenase 2 (<Emphasis Type="Italic">ALDH2</Emphasis>) genotypes with alcohol sensitivity,drinking behavior and problem drinking in Japanese older men

Objectives

Many East Asians have the genetic polymorphisms rs1229984 in alcohol dehydrogenase 1B (ADH1B) and rs671 in aldehyde dehydrogenase 2 (ALDH2). Here we analyzed the relationships of the two genotypes with alcohol sensitivity, drinking behavior and problem drinking among older and younger men living in rural areas of Japan.

Methods

The subjects were 718 Japanese men aged 63.3 ± 10.8 (mean ± SD), categorized into the older (≥65 years, n = 357) and younger (<65 years, n = 361) groups. Facial flushing frequency, drinking behavior and positive CAGE results were compared among the genotypes using Bonferroni-corrected χ² test and a multivariate logistic regression analysis adjusting for age, BMI and lifestyle factors.

Results

The frequency of ‘always’ facial flushing among the ADH1B*1/*2 carriers was significantly lower than that among the ADH1B*2/*2 carriers in the older group (P < 0.01). The alcohol consumption (unit/day) in the ADH1B*1/*2 carriers tended to be higher compared with that in the ADH1B*2/*2 carriers among the older group (P = 0.050). In the younger group, no significant differences in alcohol sensitivity and drinking habits were generally found among the ADH1B genotypes. The ADH1B*1/*1 genotype tended to be positively associated with problem drinking in the older group (P = 0.080) but not in the younger group. The ALDH2 genotypes consistently and strongly affected the alcohol sensitivity, drinking behavior and problem drinking in both the younger and older group.

Conclusions

We for the first time observed a significant difference in alcohol sensitivity between ADH1B*1/*2 and ADH1B*2/*2 in older men aged 65 and above.

     

乙醛脱氢酶2与饮酒和HBsAg致肝癌交互作用

目的：研究乙醛脱氢酶-2(ALDH2)基因多态性与饮酒习惯和HbsAg致肝癌的交互作用。方法：选择88例新发肝癌病人按性别、年龄和居住地进行1：1配对流行病学调查。病例和对照均采集静脉血，用PCR-RFLP法检测研究对象的ALDH2基因型，用ELISA法检测血中乙型肝火病毒表面抗原（HbsAg）。结果：病例组（36.40％）与对照组（35.22％）ALDH2变异基因型（G/L L/L）的分布频率无显性差异；但HbsAg阳性率病例组（72.73％）显高于对照组（22.73％）；大量饮酒、HbsAg阳性与ALDH变异基因型的交互作用指数分别为0.8320和0.6634。 结论：乙醛脱氢酶2变异基因型与大量饮酒和HbsAg阳性致肝癌发生有显的交互作用。携带ALDH2变异基因型大量饮酒将显增加患肝癌的危险性。     

乙醛脱氢酶2和细胞色素P4502E1基因多态性与甲醛职业危害易感性的关系

目的 探讨乙醛脱氢酶2(ALDH2)和细胞色素P4502E1(CYP2E1)基因多态性与甲醛职业危害易感性的关系.方法 以107例甲醛接触者外周血淋巴细胞为样本,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法测定ALDH2和CYP2E1(Rsa Ⅰ/Pst Ⅰ位点)基因型,高效液相色谱法(HPLC)检测空气中甲醛浓度和尿中甲酸含量,多组资料秩和检验分析不同ALDH2和CYP2E1基因型与甲醛接触者班末尿中代谢产物甲酸含量的关系.结果 不同ALDH2基因型影响了尿中甲酸含量,野生纯合子(GG)、杂合子(GA)、突变纯合子(AA)型个体尿中甲酸平均含量分别为(15.84±6.86)、(12.06±7.94)、(7.31±5.37)mS/S肌酐,差异有统计学意义(X2=9.241,P＜0.05),从和GG两组比较差异有统计学意义(U=26.00,P=0.033).CYP2E1基因5'-空白区域RsaⅠ/Pst Ⅰ位点多态性未影响尿中甲酸的含量,C1/C1、C1/C2、C2/C2型个体尿中甲酸平均浓度分别为:(11.14±7.91)、(12.13±8.16)、(16.51±3.78)'ng/S肌酐,差异无统计学意义(X2=4.285,P=0.117).多元回归分析变量为甲醛接触量和ALDH2基因型,模型的调整R2=0.196.结论 ALDH2外显子12上(G→A位点)多态性与人体内甲醛代谢易感性相关,而CYP2EI(Rsa Ⅰ/Pst Ⅰ位点)基因多态性与其代谢相关性无统计学意义.     

Aldehyde dehydrogenase 2 (ALDH2) genotype affects rectal cancer susceptibility due to alcohol consumption

BACKGROUND: Epidemiologic studies have shown the association between alcohol consumption and colorectal cancer, especially for rectal cancer. The alcohol related enzyme encoding gene ALDH2 has polymorphism Glu487Lys, and 487Lys allele is closely linked with phenotypic loss of enzyme activity. MATERIALS AND METHODS: A hospital-based case-control study was conducted with 72 colon and 70 rectal cancer cases and 241 non-cancer controls to evaluate the alcohol consumption and ALDH2 Glu487Lys polymorphism. The logistic regression model was applied to estimate the odds ratios (ORs). RESULT: The crude ORs for Glu/Lys and Lys/Lys genotype relative to Glu/Glu for colon and rectal cancer were not statistically significant. However, with the rectal cancer analysis, the ORs for high alcohol consumption were greater with 487Glu/Lys genotype compared with Glu/Glu, albeit not. CONCLUSIONS: These observations suggested rectal cancer risk might be influenced by ALDH2 gene polymorphism. The prevention effect by alcohol reduction might differ by ALDH2 genotype.