Benzene-metabolite-induced apoptosis: Implications of the NAD(P)H:quinone oxidoreductase 1 (NQO1) C609T polymorphism for susceptibility of hematopoietic cells to phenolic metabolite

Exposure to benzene results in various hematotoxicities including aplastic anemia. Depletion of bone marrow progenitor cells, probably via increased apoptosis, may play a role in the pathogenesis of aplastic anemia. Here we investigated the ability of several benzene metabolites to induce apoptosis in hematopoietic cells. Hydroquinone (HQ), 1,2,4-benzenetriol, catechol (CAT), trans, trans-muconaldehyde, and 6-hydroxy-2,4-hexadienal, but not phenol or muconic acid induced apoptosis in HL-60 cells. HQ also induced concentration-dependent apoptosis in KG-1a cells and primary human hematopoietic progenitor cells (HPC's). These data suggest that several benzene metabolites are capable of inducing apoptosis in hematopoietic cells and that HQ at least, can directly induce apoptosis in HPC's. Following benzene exposure, benzene metabolites may induce excess apoptosis in HPC's, eventually depleting immature precursors and contributing to the development of aplastic anemia. Phenolic metabolites are bioactivated by myeloperoxidase (MPO) to yield the corresponding quinones which may contribute to benzene hematotoxicity. NAD(P)H:quinone oxidoreductase 1 (NQO1) plays a protective role in benzene hematotoxicity. A polymorphism in the coding region of NQO1 (C609T) has been characterized which results in a lack of NQO1 in homozygous cells. Benzene exposed workers with this genotype were at an increased risk of hematotoxicity, an observation difficult to reconcile with the lack of constitutive NQO1 expression in HPC's. HQ induced NQO1 protein and activity in primary human bone marrow cells wild type or heterozygous for the C609T substitution, but not in cells homozygous for the C609T substitution. HQ also induced NQO1 protein and activity in wild type HPCs. Pretreatment of KG-1a cells with a noncytotoxic concentration of HQ induced NQO1 protein and activity and thiols, and reduced apoptosis induced by subsequent higher doses of HQ. The results of these studies suggest that NQO1 is induced in HPC's following benzene exposure where it acts in concert with other protective mechanisms to reduce quinone-induced apoptosis. In individuals carrying the homozygous NQO1 C609T substitution, NQO1 is not induced following benzene exposure and the lack of NQO1 increases the susceptibility of HPC's to benzene metabolite toxicity.