Abstract

Although benzene requires metabolic activation in order to exert its myelotoxic effects, the metabolic mechanisms underlying toxicity are not defined. Bone marrow stroma has been implicated as a potential target of benzene metabolites. Stroma represents a hemopoietic microenvironment which is critical to the regulation of normal hemopoiesis. Toxic effects of benzene at the level of bone marrow stroma provide a potential mechanism for benzene-induced myelotoxicity and leukemogenicity. The experiments proposed will focus on the metabolism and toxicity of benzene and its metabolites at the level of the target organ, the bone marrow. More specifically mechanisms of toxicity at the level of bone marrow stroma will be investigated. Studies of metabolic activation and detoxification of benzene and its metabolites will be combined with an analysis of the effects of benzene and its metabolites on stromal-derived regulators of differentiation and proliferation. The effects of benzene and its metabolites on eicosanoid and lymphokine homeostasis in murine bone marrow stroma will be examined together with effects on proteases responsible for lymphokine processing. In order to assess the relevance of any effects observed in-vitro, whether similar effects are observed after benzene administration to mice in-vivo will also be examined. Metabolic and mechanistic studies will also be extended to the human situation by examining the effect of benzene and its metabolites on human bone marrow and stroma in-vitro.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004112-08
Application #
2153569
Study Section
Safety and Occupational Health Study Section (SOH)
Project Start
1986-07-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Type
Schools of Pharmacy
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Moran, J L; Siegel, D; Sun, X M et al. (1996) Induction of apoptosis by benzene metabolites in HL60 and CD34+ human bone marrow progenitor cells. Mol Pharmacol 50:610-5
Ross, D; Siegel, D; Schattenberg, D G et al. (1996) Cell-specific activation and detoxification of benzene metabolites in mouse and human bone marrow: identification of target cells and a potential role for modulation of apoptosis in benzene toxicity. Environ Health Perspect 104 Suppl 6:1177-82
Ross, D (1996) Metabolic basis of benzene toxicity. Eur J Haematol Suppl 60:111-8
Miller, A C; Schattenberg, D G; Malkinson, A M et al. (1994) Decreased content of the IL1 alpha processing enzyme calpain in murine bone marrow-derived macrophages after treatment with the benzene metabolite hydroquinone. Toxicol Lett 74:177-84
Levay, G; Ross, D; Bodell, W J (1993) Peroxidase activation of hydroquinone results in the formation of DNA adducts in HL-60 cells, mouse bone marrow macrophages and human bone marrow. Carcinogenesis 14:2329-34
Goon, D; Saxena, M; Awasthi, Y C et al. (1993) Activity of mouse liver glutathione S-transferases toward trans,trans-muconaldehyde and trans-4-hydroxy-2-nonenal. Toxicol Appl Pharmacol 119:175-80
Goon, D; Matsuura, J; Ross, D (1993) Metabolism and cytotoxicity of trans,trans-muconaldehyde and its derivatives: potential markers of benzene ring cleavage reactions. Chem Biol Interact 88:37-53
Ganousis, L G; Goon, D; Zyglewska, T et al. (1992) Cell-specific metabolism in mouse bone marrow stroma: studies of activation and detoxification of benzene metabolites. Mol Pharmacol 42:1118-25
Monks, T J; Hanzlik, R P; Cohen, G M et al. (1992) Quinone chemistry and toxicity. Toxicol Appl Pharmacol 112:2-16
Goon, D; Cheng, X; Ruth, J A et al. (1992) Metabolism of trans,trans-muconaldehyde by aldehyde and alcohol dehydrogenases: identification of a novel metabolite. Toxicol Appl Pharmacol 114:147-55

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