DISTINCT ACTIONS OF BENZENE AND ITS METABOLITES ON NITRIC-OXIDE PRODUCTION BY BONE-MARROW LEUKOCYTES

Benzene is a widely used industrial solvent known to cause bone marrow depression. This is associated with increased production of reactive oxygen metabolites and nitric oxide by bone marrow phagocytes, which h ave been implicated in hematotoxicity. Benzene metabolism to phenolic intermediates appears to be an important factor in bone marrow toxicit y. In the present studies, we compared the effects of benzene and seve ral of its metabolites on nitric oxide production by murine bone marro w leukocytes. Bone marrow cells readily produced nitric oxide in respo nse to the inflammatory mediators lipopolysaccharide (LPS) and interfe ron-gamma (IFN-gamma). Treatment of mice with benzene (800 mg/kg), or its metabolites hydroquinone (100 mg/kg), 1,2,4-benzenetriol (25 mg/kg ), or p-benzoquinone (2 mg/kg), at doses that impair hematopoiesis, se nsitized bone marrow leukocytes to produce increased amounts of nitric oxide in response to LPS and IFN-gamma. Granulocyte-macrophage colony -stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) augmented bone marrow leukocyte production of nitric oxide ind uced by inflammatory mediators. Benzene, as well as its metabolites, m arkedly increased the sensitivity of the cells to both GM-CSF and M-CS F. Cells from hydroquinone- or 1,2,4-benzenetriol-treated mice were si gnificantly more responsive to the inflammatory cytokines and growth f actors than cells isolated from benzene- or p-benzoquinone-treated mic e, suggesting that the phenolic metabolites of benzene are important b iological reactive intermediates. Because nitric oxide suppresses cell growth and can be metabolized to mutagens and carcinogens, the abilit y of benzene and its metabolites to modulate its production in the bon e marrow may be important in their mechanism of action.