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， 遗传毒性和致癌性的一些产业工人接触高水平。 虽然许多研究表明，苯引起几个造血 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， NAD（P）H：醌氧化还原酶-1（NQO 1）与 苯中毒和白血病的发病率。NQO 1解毒建议 苯的血液毒性代谢物。某些少数民族，如亚洲人， NQO 1基因第6号外显子多态性导致缺失的比例很高 NQO 1活性。NQO 1最近被证明参与调节 p53是一种参与DNA损伤反应途径的肿瘤抑制基因， 抑制其降解。我们的实验室先前已经表明， 参与p53反应途径的基因，如细胞周期和 细胞凋亡，在苯暴露的小鼠中改变。要解决的假设 在这项研究中，NQO 1缺乏导致增强苯诱导的 血液毒性和遗传毒性。具有外显子6的功能性NQO 1缺失的小鼠 已经开发了从NQO 1基因缺失的基因。拟议的研究将 将NQO 1-/-和野生型小鼠暴露于吸入的苯中， 以剂量依赖性方式测定：（1）NQO 1-/-小鼠对以下物质的易感性： 与野生型小鼠相比，苯诱导的血液毒性，以及（2）p53 DNA NQO 1-/-与野生型小鼠对苯的损伤反应。的 本研究的最终目的是为了更好地了解 苯血液毒性的机制，开发生物标志物，以确定那些 基因上对苯更敏感的人。

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.