Nivard M J, Wijen J, Vogel E W
Department of Radiation Genetics and Chemical Mutagenesis, Medical Genetics Centre South-West Netherlands, University of Leiden.
Acta Biochim Pol. 1998;45(2):545-59.
Genotoxic carcinogens, able to damage DNA by alkylation reactions, represent a very diverse class of agents which are capable of producing a wide range of DNA modifications. The mechanisms leading to genetic changes as a result of exposure to alkylating agents (AAs) have been studied in male germ cells of Drosophila using a structure-activity relationship approach (SAR). The analytical tools available concern both genetic and molecular assays. The genetic tests enable to quantify excision repair and clastogenic potency of the AA after treatment of post-meiotic male germ cells and to determine the degree of germ-cell specificity, i.e., the mutagenic effectiveness in post- versus premeiotic cell stages. For a selected group of alkylating agents the molecular spectra have been studied in post-meiotic cell stages. On the basis of these descriptors clear SAR's between genotoxic activity in germ cells and physico-chemical parameters (s-values and O6/N7-alkylguanine adducts) and carcinogenic potency in rodents became apparent, resulting in five distinct classes of alkylating agents so far. These classes are: 1) SN2-type monofunctional AAs, 2) SN1-type monofunctional AAs, 3) polyfunctional AAs, 4) agents able to form etheno-DNA adducts, and 5) aflatoxin B1 (AFB1) a bulky-adduct forming agent. The recent finding that the molecular data obtained with Drosophila and data of the specific locus tests in male mice show remarkable similarities for most genotoxic agents supports the view that Drosophila is a useful model system for the study of transgenerational damage.
遗传毒性致癌物能够通过烷基化反应损伤DNA，它们是一类非常多样的物质，能够产生广泛的DNA修饰。利用构效关系方法（SAR），在果蝇的雄性生殖细胞中研究了因接触烷基化剂（AAs）而导致基因变化的机制。现有的分析工具涉及遗传和分子检测。遗传检测能够量化减数分裂后雄性生殖细胞经AA处理后的切除修复和致断裂能力，并确定生殖细胞特异性程度，即减数分裂后与减数分裂前细胞阶段的诱变效力。对于一组选定的烷基化剂，已经在减数分裂后细胞阶段研究了分子光谱。基于这些描述符，生殖细胞中的遗传毒性活性与物理化学参数（s值和O6/N7-烷基鸟嘌呤加合物）以及啮齿动物中的致癌能力之间清晰的构效关系变得明显，到目前为止产生了五类不同的烷基化剂。这些类别是：1）SN2型单功能AAs，2）SN1型单功能AAs，3）多官能AAs，4）能够形成乙烯基-DNA加合物的试剂，以及5）黄曲霉毒素B1（AFB1），一种形成大体积加合物的试剂。最近的发现表明，用果蝇获得的分子数据与雄性小鼠特定基因座测试的数据对于大多数遗传毒性剂显示出显著的相似性，这支持了果蝇是研究跨代损伤的有用模型系统的观点。
