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.
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