THE ROLE OF NQO1 IN BENZENE-INDUCED HEMATOTOXICITY

NQO1 在苯引起的血液毒性中的作用

• 批准号: 6445330
• 负责人: ALISON K BAUER
• 金额: $ 1.74万
• 依托单位: THE HAMNER INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2002-06-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6445330
• 关键词: NAD(P)H oxidoreductase; apoptosis; benzene; biomarker; blood toxicology; cell cycle; chemical carcinogen; chemical kinetics; complementary DNA; drug administration rate /duration; environmental toxicology; enzyme deficiency; gene expression; genetic susceptibility; inhalation drug administration; laboratory mouse; leukemia; microarray technology; p53 gene /protein; pharmacokinetics; postdoctoral investigator; quinones

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.

描述（由申请人提供）：苯已被证明具有血液毒性， 某些接触高浓度的产业工人具有遗传毒性和致癌性。 尽管许多研究表明苯会导致多种造血功能障碍 苯引起的疾病，例如人类白血病，的机制 对血液毒性和致癌性知之甚少。在人类中，失去 NAD(P)H：醌氧化还原酶-1 (NQO1) 与 苯中毒和白血病的发生率。 NQO1 解毒提议 苯的血液毒性代谢物。某些种族人群，例如亚洲人， NQO1 基因的外显子 6 具有高比例的多态性，导致丢失 NQO1 活性。 NQO1 最近被证明参与调节 p53，一种参与 DNA 损伤反应途径的肿瘤抑制基因， 抑制其降解。我们的实验室之前已经表明，一些 参与 p53 反应途径的基因，例如细胞周期和 苯暴露小鼠的细胞凋亡发生改变。待解决的假设 在这项研究中，NQO 1 缺乏会导致苯诱导的 血液毒性和遗传毒性。缺乏外显子 6 功能性 NQO1 的小鼠 已开发出从 NQO1 基因删除的。拟议的研究将 将 NQO1-/- 和野生型小鼠暴露于吸入苯一段时间内 剂量依赖性方式确定：（1）NQO1-/-小鼠对 与野生型小鼠相比，苯引起的血液毒性，以及 (2) p53 DNA NQO1-/- 与野生型小鼠对苯的损伤反应。这 本研究的最终目标是更好地了解 苯血液毒性机制，开发生物标志物来识别苯血液毒性 个体在遗传上对苯更敏感。