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，

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.