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.
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