Chronic exposure to benzene, an extensively used industrial chemical and widespread environmental contaminant, results in progressive deterioration of haematopoietic function, acute myelogenous leukemia and lymphoma in man. The mechanisms underlying benzene-induced myelotoxicity are unknown but metabolism of benzene is required for it to induce toxic effects. The major metabolite of benzene is phenol but myelotoxicity has been correlated with bone marrow concentrations of the secondary benzene metabolites - catechol and hydroquinone. No information exists concerning activation of catechol or hydroquinone to reactive species by bone marrow cells or by enzymes present in high concentration in bone marrow such as myeloperoxidase (MPO). We therefore propose to examine the metabolism of benzene and its phenolic metabolites by rat and human MPO and by various rat bone marrow cell populations. Use of both MPO and bone marrow cells will allow us to compare metabolite profiles produced by the isolated enzyme and by the cellular systems and to observe the biochemical changes associated with cytotoxicity in bone marrow cells. We also propose to examine whether MPO-catalyzed oxidation of the phenolic metabolites of benzene results in the production of species which can bind to cellular macromolecules (DNA, protein, glutathione) and if so to characterize any DNA or glutathione adducts that are formed. The contribution of autoxidation reactions of phenolic metabolites of benzene and more specifically, the production of active oxygen species to cytotoxocity in cellular systems will be examined, as will the role of other potential toxifying and detoxifying enzymes in bone marrow cells. As one of the most sensitive cell populations to benzene-induced toxicity is peripheral leukocytes, we propose to examine the activation of benzene and its metabolites to binding species when incubated with leukocytes stimulated to perform an oxidative burst. This work should greatly increase our understanding of the metabolic mechanisms underlying benzene-induced myelotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004112-03
Application #
3252061
Study Section
Safety and Occupational Health Study Section (SOH)
Project Start
1986-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1990-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Colorado at Boulder
Department
Type
Schools of Pharmacy
DUNS #
City
Boulder
State
CO
Country
United States
Zip Code
80309
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

Showing the most recent 10 out of 19 publications