NAD(P)H:quinone oxidoreductase (NQO1) is known to protect against benzene-induced hematopoietic toxicity. The proposed mechanism is protection against reactive benzene-derived quinones and oxygen radicals formed in bone marrow. The major problem with this mechanism is that NQO1 levels are non-detectable in human bone marrow aspirates. This observation is inconsistent with a proposed protective role for NQO1 in human bone marrow and the increased benzene-induced hematotoxicity observed in individuals carrying a homozygous NQO1 mutation which results in the absence of NQO1 activity. The investigator will test the following two hypotheses in this proposal which could provide an adequate explanation for the protective effects of NQO1 against benzene toxicity. Hypothesis 1. Stromal microenvironments exist in-situ in human bone marrow which have significant NQO1 activity and are not removed by bone marrow aspiration. They propose that individuals carrying the homozygous NQO1 mutation would not have stromal NQO1 leading to impaired detoxification by NQO1. Hypothesis 2. The mechanism underlying the protective effect of NQO1 against benzene-induced hematotoxicity is that NQO1 can be induced in bone marrow by benzene metabolites. In individuals carrying the homozygous NQO1 mutation, however, NQO1 activity is not induced after exposure to benzene metabolites leading to impaired detoxification and chemoprotection. This hypothesis will be tested by characterizing induction of NQO1 by benzene metabolites in the human hematopoietic cell line KG-1a, in human bone marrow and potential target cells such as stroma and CD34+ progenitor cells. The molecular mechanism underlying induction of NQO1 by benzene metabolites will be examined and the investigators will confirm that the toxicity of benzene metabolites is ameliorated by NQO1 induction in human bone marrow. These experiments will provide a mechanistic explanation for the protective effects of NQO1 against benzene-induced hematopoietic toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES009554-01
Application #
2690731
Study Section
Special Emphasis Panel (ZRG4-ALTX-4 (01))
Project Start
1998-07-15
Project End
2001-06-30
Budget Start
1998-07-15
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
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
Ross, David; Zhou, Hongfei (2010) Relationships between metabolic and non-metabolic susceptibility factors in benzene toxicity. Chem Biol Interact 184:222-8
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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