THE ROLE OF NQO1 IN BENZENE-INDUCED HEMATOTOXICITY

描述(由申请人提供)：苯已被证明具有血液毒性， 在一些暴露在高水平下的产业工人中，有遗传毒性和致癌作用。 尽管许多研究表明，苯会导致几种造血剂 疾病，如人类白血病，苯诱导的机制 血液毒性和致癌性知之甚少。在人类中，丧失 NAD(P)H：苯醌氧化还原酶-1(NQO1)与 苯中毒和白血病的发生率。NQO1为建议的 苯的血液毒性代谢物。某些民族人口，如亚洲人， NQO1基因外显子6有很高的多态导致丢失 NQO1活性。NQO1最近被证明参与调节 P53，一种参与DNA损伤反应通路的肿瘤抑制基因，通过 抑制其降解。我们的实验室之前已经证明，一些 参与P53反应途径的基因，如细胞周期和 细胞凋亡，在苯暴露的小鼠中发生改变。需要解决的假设 在本研究中，NQO-1缺乏导致苯诱导的增强 血液毒性和遗传毒性。外显子6缺失功能性NQO1的小鼠 从NQO1基因中删除的基因已经被开发出来。拟议的研究将 在一段时间内将NQO1/-和野生型小鼠暴露于吸入的苯-和 以剂量依赖的方式确定：(1)NQO1-/-小鼠对 苯诱导的血液毒性与野生型小鼠的比较，以及(2)P53 DNA NQO1-/-与野生型小鼠对苯的损伤反应。这个 这项研究的最终目的是为了更好地了解 苯的血液毒性机制研究进展 在基因上更容易受到苯影响的个体。

DESCRIPTION (provided by applicant): Benzene has been shown to be hematotoxic, genotoxic, and carcinogenic in some industrial workers exposed to high levels. Although many studies have shown that benzene causes several hematopoietic disorders, such as leukemias in humans, the mechanism of benzene-induced hematotoxicity and carcinogenicity is poorly understood. In humans, loss of NAD(P)H: quinone oxidoreductase-1 (NQO1) is associated with an increased incidence of benzene poisoning and leukemias. NQO1 detoxifies the proposed hematotoxic metabolite of benzene. Certain ethnic populations, such as Asians, have a high rate of a polymorphism in exon 6 of the NQO1 gene leading to loss of NQO1 activity. NQO1 has recently been shown to be involved in regulating p53, a tumor suppressor gene involved in DNA damage response pathways, by inhibiting its degradation. Our laboratory has previously shown that some of the genes involved in the p53 response pathway, such as cell cycle and apoptosis, are altered in benzene-exposed mice. The hypothesis to be addressed in this study is that NQO 1 deficiency leads to enhanced benzene-induced hematotoxicity and genotoxicity. Mice lacking functional NQO1 with exon 6 deleted from the NQO1 gene have been developed. The proposed studies will expose NQO1-/- and wild-type mice to inhaled benzene in a time- and dose-dependent manner to determine: (1) the susceptibility of NQO1-/- mice to benzene-induced hematotoxicity compared to wild-type mice, and (2) the p53 DNA damage response in NQO1-/- vs. wild-type mice in response to benzene. The ultimate goal of this study is to attain a better understanding of the mechanism of benzene hematotoxicity to develop biomarkers to identify those individuals more genetically susceptible to benzene.