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.
National Institute of Environmental Health Sciences
CFDA Code
DUNS Number
007431505
UEI
SPVKK1RC2MZ3
Project Start Date
01-July-1986
Project End Date
30-June-1989
Budget Start Date
01-July-1987
Budget End Date
30-June-1988
Project Funding Information for 1987
Total Funding
$83,738
Direct Costs
$59,305
Indirect Costs
$24,433
Year
Funding IC
FY Total Cost by IC
1987
National Institute of Environmental Health Sciences
$83,738
Year
Funding IC
FY Total Cost by IC
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