Abstract

The metabolic basis of benzene induced myelotoxicity remains poorly understood. We have examined bioactivation of the secondary phenolic metabolites of benzene in the target organ of benzene's toxicity - the bone marrow. We propose to extend this work to examine quantitative and enzymological aspects of bioactivation in specific cell types - unpurified white bone marrow cells, macrophages, neutrophilic cells and stromal fibroblasts. We will examine enzymology responsible for activation and deactivation of phenolic metabolites of benzene and trans muconaldehyde in specific cell types. We also propose to determine whether metabolites of benzene alter prostaglandin production in specific cells since eiconsanoids are important regulators of hemopoiesis. Interactions between phenolic metabolites of benzene will be examined in specific cells. The formulation of DNA adducts from phenolic metabolites of benzene and trans muconaldehyde will be examined in specific cells using HPLC and 32P methodology. This work should greatly increase our understanding of the metabolic mechanisms underlying benzene-induced myelotoxicity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES004112-04A1
Application #
3252058
Study Section
Safety and Occupational Health Study Section (SOH)
Project Start
1986-07-01
Project End
1993-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
University of Colorado at Boulder
Department
Type
Schools of Pharmacy
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309

  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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