Genetic polymorphisms in human xenobiotica metabolizing enzymes as susceptibility factors in toxic response
Genetic polymorphisms in human xenobiotica metabolizing enzymes as susceptibility factors in toxic response
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DOI：
10.1016/s1383-5718(99)00167-9
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发表时间：
2000-01-03
影响因子：
1.9
通讯作者：
Autrup, H
中科院分区：
文献类型：
--
作者：
Autrup, H
生物转化在环境致癌物的致癌活性和器官特异性中起着重要作用。大的个体间差异的生物转化已被报道，和遗传多态性的一些异生物质代谢酶可以部分解释这些差异。与DNA反应的最终致癌物的浓度取决于活化和解毒的速率。解毒率下降的个人，即，缺乏谷胱甘肽S-转移酶M1基因，在某些组织中具有稍高水平的大量致癌物-DNA加合物，并且染色体畸变水平也确实增加。此外，基因型也可能影响突变的类型，例如，在抑癌基因中，GSTM 1缺失组以颠换为主。具有慢N-乙酰转移酶活性的人通常在膀胱组织中具有较高的芳香胺加合物水平。CYP 1A 1或谷胱甘肽S-转移酶的遗传多态性与吸烟相关癌症的风险增加有关，而N-乙酰转移酶活性与芳香胺是主要风险因素的癌症有关。活化和解毒酶的高风险基因型的组合，例如，CYP 1A MspI/GSTM 1 null不仅与癌症发展风险增加相关，而且与生物活性剂量标记物和早期效应标记物水平增加相关。为了确定有毒化合物的指导值，必须进一步研究外源物质代谢酶的遗传变异及其组合在相关低接触水平下的作用。(C)2000爱思唯尔科技有限公司。保留所有权利。
Biotransformation plays an important role in the carcinogenic activity and organ specificity of environmental carcinogens. Large interindividual variation in the biotransformation has been reported, and genetic polymorphisms in some xenobiotica metabolizing enzymes can in part explain some of these differences. The concentration of the ultimate carcinogen, that will react with DNA, is determined by the rate of activation and detoxification. Individuals with a decreased rate of detoxification, i.e., lacking the glutathione S-transferase M1 gene, have a slightly higher level of bulky carcinogen-DNA adduct in some tissues, and do also have an increased level of chromosomal aberrations. In addition, the genotype may also influence the type of mutations, e.g., in tumor suppressor gene, transversion being predominant in the GSTM1 null group. People with slow N-acetyltransferase activity do generally have a higher adduct level of aromatic amines in bladder tissues. Genetic polymorphism in either CYP1A1 or glutathione S-transferase is linked to an increased risk of smoking related cancers, while N-acetyltransferase activity is related to cancers in which aromatic amines are the main risk factor. Combination of the high risk genotypes for activating and detoxification enzymes, e.g., CYP1A MspI/GSTM1 null is not only associated with an increased risk of cancer development, but also an increased level of markers of the biological active dose and early markers of effect. Additional studies on the role of genetic variants of xenobiotica metabolizing enzymes and combinations thereof at relevant low levels of exposure are important in order to establish guidance values for toxic compounds. (C) 2000 Elsevier Science B.V. All rights reserved.