GENOTOXICITY OF BENZO[A]PYRENE DERIVATIVES AND SULFITE

二氧化硫，一种无处不在的空气污染物，也是烟草的一种成分 吸烟，是呼吸道中苯并[a]芘（BP）的辅助致癌物 道。 我们研究了亚硫酸盐的影响， 二氧化硫对BP代谢和遗传毒性的影响 代谢物。 该提案侧重于亚硫酸盐与 7，8-二羟基-7，8-二氢苯并[a]芘（BP-7，8-二醇）和 7r，8t-dihydroxy-9t，10t-epoxy7，8，9，10-tetrahydrobenzo[a]pyrene（anti-BPDE） 形成同分异构的湾区BPT磺酸盐。 这些衍生物，形成于 在与S.鼠伤寒试验菌株或 与仓鼠气管在器官培养，代表了一类新的 活性中间体 虽然远比水解稳定， 尽管如此，这些磺酸盐仍然共价结合到bay区域二醇环氧化物上， DNA水平与二醇环氧化物相当。 基于 我们的发现，我们已经开发并将测试的假设， 遗传毒性BPT磺酸盐的形成代表了一种机制， 二氧化硫增强BP致癌性。 这个项目的总体目标是 应用是表征生物化学和生物学因素 影响BPT磺酸盐的形成及其生物活性 活动 化学表征将检查BPT的反应性 与DNA、RNA和蛋白质的磺酸盐。 由于DNA的重要性 突变和致癌作用中的修饰， 将通过32 p-后标记和 脱氧核苷加合物结构表征。 在所有情况下， 将磺酸盐的行为与抗BPDE的行为进行比较。 的 这些BPT磺酸盐在生物系统中形成的能力，及其 将使用V79仓鼠肺细胞检查对这些系统的影响 线 V79细胞将用含和不含亚硫酸盐的抗BPDE处理， 或BPT磺酸盐，以及所得BP产物分布和 与细胞大分子共价结合的诱导将是 测定 最后，BPT磺酸盐的遗传毒性活性将是 在V79系统中使用hgprt表型的选择来确定。 该项目的主要目的是描述化学品的特性， BPT磺酸盐的生物学特性，这代表了一类新的 活性中间体 如果这些产品很容易形成完整的 哺乳动物细胞，如果它们容易修饰细胞核酸，并且如果 它们在这个系统中发挥遗传毒性作用， 观察到二氧化硫对BP致癌作用的增强作用， 将建立。

Sulfur dioxide, a ubiquitous air pollutant and a component of tobacco smoke, is a cocarcinogen for benzo[a]pyrene (BP) in the respiratory tract. We have investigated effects of sulfite, the physiological form of sulfur dioxide, on the metabolism and the genotoxicity of BP metabolites. This proposal focuses on interactions of sulfite with 7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) and 7r,8t-dihydroxy-9t,10t-epoxy7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) to form isomeric bay-region BPT sulfonates. These derivatives, formed in high yield in incubations with either S. typhimurium tester strains or with hamster trachea in organ culture, represent a novel class of reactive intermediates. Although far more stable to hydrolysis than are bay-region diolepoxides, these sulfonates nevertheless bind covalently to DNA at levels comparable to those seen with the diolepoxides. Based on our findings, we have developed and will test the hypothesis that formation of genotoxic BPT sulfonates represents a mechanism by which sulfur dioxide enhances BP carcinogenicity. The overall goal of this application is to characterize the biochemical and biological factors affecting both the formation of BPT sulfonates and their biological activities. Chemical characterization will examine the reactivity of BPT sulfonates with DNA, RNA, and protein. Due to the importance of DNA modification in mutagenesis and carcinogenesis, the interactions of the sulfonates with DNA will be studied by both 32p-postlabeling and structural characterization of deoxynucleoside adducts. In all cases, behavior of the sulfonates will be compared with that of anti-BPDE. The ability of these BPT sulfonates to form in biological systems, and their effects on these systems will be examined using the V79 hamster lung cell line. V79 cells will be treated with anti-BPDE with and without sulfite, or with BPT sulfonates, and the resultant BP product profile and the induction of covalent binding to cellular macromolecules will be determined. Finally, the genotoxic activity of BPT sulfonates will be determined in the V79 system using selection for the hgprt phenotype. The primary aim of this project is to characterize the chemical and biological properties of BPT sulfonates, which represent a novel class of reactive intermediates. If these products are formed readily in intact mammalian cells, if they readily modify cellular nucleic acids, and if they exert genotoxic effects in this system, then a process consistent with the observed enhancing effect of sulfur dioxide on BP carcinogenesis will be established.