The homozygous NQO1*2 polymorphism results in a total lack of NQO1 activity due to accelerated degradation of the mutant NQO1*2 protein by the ubiquitin/proteasomal pathway. The NQO1*2 polymorphism has been found to be a risk factor for benzene-induced myeloid toxicity but also for childhood and adult de-novo leukemias and secondary leukemias arising as a result of chemotherapy. The mechanisms underlying the protective effects of NQO1 against benzene-induced myelotoxicity and both de-novo and secondary leukemias were puzzling since NQO1 was not expressed in aspirated human bone marrow cells or human bone marrow CD34+ progenitor cells, the target cell for induction of both aplastic anemia and leukemia. However, we observed that NQO1 was present in human bone marrow endothelial cells (HBMEC), which are not harvested by bone marrow aspiration. In the present application, we wish to explore the potential role of NQO1 in HBMEC in protection against benzene induced aplastic anemia and have established HBMEC cultures in our lab for this purpose. We propose a mechanism whereby HBMEC exposed to benzene metabolites produce increasing amounts of endothelial IL8 (elL8) which results in apoptosis of neighboring hematopoietic cells and myeloid progenitor cells resulting in aplastic anemia. We will also examine the mechanism underlying the lack of expression of NQO1 in human myeloid cells at the transcriptional level by characterizing cis acting DNA sequences and trans acting nuclear protein-DNA interactions that modulate NQO1 expression. One of the major tumor suppressor genes characterized in mammalian systems is p53 and a high percentage of leukemias contain mutations or allelic losses of p53. In preliminary data, we demonstrate that NQO1 forms a protein complex with wild type p53. We propose to examine whether the interaction of NQO1 and p53 is specific for wild type p53 and whether it has consequences for p53 stability and p53-dependent transcriptional activation of downstream genes. If NQO1 stabilizes p53 and the interaction has functional consequences, this would provide a mechanism for the increased incidence of leukemia of diverse origin that has been associated with a lack of NQO1 protein due to the NQO1*2 polymorphism.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Humble, Michael C
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University of Colorado Denver
Schools of Pharmacy
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Ross, David; Zhou, Hongfei; Siegel, David (2011) Benzene toxicity: The role of the susceptibility factor NQO1 in bone marrow endothelial cell signaling and function. Chem Biol Interact 192:145-9
Ross, David; Zhou, Hongfei (2010) Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity. Chem Biol Interact 184:222-8
Zhou, Hongfei; Dehn, Donna; Kepa, Jadwiga K et al. (2010) NAD(P)H:quinone oxidoreductase 1-compromised human bone marrow endothelial cells exhibit decreased adhesion molecule expression and CD34+ hematopoietic cell adhesion. J Pharmacol Exp Ther 334:260-8
Zhou, Hongfei; Kepa, Jadwiga K; Siegel, David et al. (2009) Benzene metabolite hydroquinone up-regulates chondromodulin-I and inhibits tube formation in human bone marrow endothelial cells. Mol Pharmacol 76:579-87
Stagos, Dimitrios; Zhou, Hongfei; Ross, David et al. (2009) 4-HNE inhibits tube formation and up-regulates chondromodulin-I in human endothelial cells. Biochem Biophys Res Commun 379:654-8
Vasiliou, Vasilis; Ross, David; Nebert, Daniel W (2006) Update of the NAD(P)H:quinone oxidoreductase (NQO) gene family. Hum Genomics 2:329-35
Inayat-Hussain, Salmaan H; Ross, David (2005) Intrinsic pathway of hydroquinone induced apoptosis occurs via both caspase-dependent and caspase-independent mechanisms. Chem Res Toxicol 18:420-7
Ross, David (2005) Functions and distribution of NQO1 in human bone marrow: potential clues to benzene toxicity. Chem Biol Interact 153-154:137-46
Ross, David (2004) Quinone reductases multitasking in the metabolic world. Drug Metab Rev 36:639-54
Bironaite, Daiva; Siegel, David; Moran, Julie L et al. (2004) Stimulation of endothelial IL-8 (eIL-8) production and apoptosis by phenolic metabolites of benzene in HL-60 cells and human bone marrow endothelial cells. Chem Biol Interact 149:37-49

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