BENZENE TOXICITY AND METABOLISM

本提案的目的是调查 苯代谢产物的产生及苯中毒的病因 骨髓抑制和白血病 苯的完整途径 将在CD-1、C57 B1/6和DBA/2小鼠中研究代谢，Sprague 道利大鼠和家兔在体内和体外使用3 H和14 C-苯。 在 除了分析羟基化环代谢物的形成，我们 将寻求开环产品和二氧化碳的生产， 苯 不同的菌株和物种将被使用，因为我们有 确定了大鼠和小鼠对苯的敏感性差异， 现在计划探索兔子的敏感性。 每一个人的新陈代谢 这些模型将与灵敏度一起进行沿着比较。 计划进行研究 探讨共价结合与可溶性代谢物的意义 以及从毒性到持久性的相关恢复 代谢物。 我们还计划研究苯对核酸的影响 线粒体和细胞核的代谢。 发现苯 抑制线粒体RNA和蛋白质合成，同时共价结合 线粒体DNA，我们计划确定是否同样发生在 原子核 特别有趣的是苯似乎是 在线粒体中被代谢激活。 我们计划研究 和骨髓线粒体中的共价结合， 毒性。 最后，我们计划研究混合功能氧化酶 在线粒体和细胞核中负责苯的代谢。

The aims of this proposal are to investigate the relationship between the production of metabolites of benzene and the etiology of benzene-induced bone marrow depression and leukemia. The complete pathway of benzene metabolism will be investigated in CD-1, C57B1/6 and DBA/2 mice, Sprague Dawley rats and rabbits in vivo and in vitro using 3H and 14C-benzene. In addition to analyzing the formation of hydroxylated ring metabolites, we will seek ring opening products and carbon dioxide production from benzene. The different strains and species will be used because we have defined the differences in sensitivity to benzene by the rats and mice and now plan to explore the sensitivity of the rabbit. Metabolism in each of these models will be compared along with sensitivity. Studies are planned to explore the significance of covalently bound versus soluble metabolites and to related recovery from toxicity to persistence of both types of metabolites. We also plan to study the effects of benzene on nucleic acid metabolism in both mitochondria and nuclei. Having found that benzene inhibits mitochondrial RNA and protein synthesis while covalently binding to mitochondrial DNA, we plan to determine whether the same occurs in the nucleus. Of special interest was the finding that benzene appears to be metabolically activated in mitochondria. We plan to study the metabolism and the covalent binding in mitochondria of bone marrow which is the site of toxicity. Finally, we plan to investigate the mixed function oxidases in mitochondria and nuclei which are responsible for benzene metabolism.