Distinct actions of benzene and its metabolites on nitric oxide production by bone marrow leukocytes

Abstract

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 have been implicated in hematotoxicity. Benzene metabolism to phenolic intermediates appears to be an important factor in bone marrow toxicity. In the present studies, we compared the effects of benzene and several of its metabolites on nitric oxide production by murine bone marrow leukocytes. Bone marrow cells readily produced nitric oxide in response to the inflammatory mediators lipopolysaccharide (LPS) and interferon-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, sensitized 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 induced by inflammatory mediators. Benzene, as well as its metabolites, markedly increased the sensitivity of the cells to both GM-CSF and M-CSF. Cells from hydroquinone- or 1,2,4-benzenetriol-treated mice were significantly more responsive to the inflammatory cytokines and growth factors than cells isolated from benzene- or p-benzoquinone-treated mice, suggesting that the phenolic metabolites of benzene are important biological reactive intermediates. Because nitric oxide suppresses cell growth and can be metabolized to mutagens and carcinogens, the ability of benzene and its metabolites to modulates its production in the bone marrow may be important in their mechanism of action.

Role of nitric oxide in hematosuppression and benzene-induced toxicity.

“…Moreover, nitric oxide production by bone marrow cells is inversely correlated with cellular proliferation. Cells from benzenetreated mice exhibited increased sensitivity to nitric oxide-mediated growth inhibition, a finding consistent with the idea that nitric oxide contributes to the reduced bone marrow cellularity and impaired hematopoiesis observed after benzene exposure (7,22,23 25 mg/kg 1 ,2,4-benzenetriol, 2 mg/kg p-benzoquinone, or corn oil control once/day for 3 days or twice/day for 2 days. These treatment protocols were found to induce bone marrow suppression (24)(25)(26).…”

“…Cells from hydroquinone or 1,2,4-benzenetriol treated mice produced more nitric oxide than cells from benzene or p-benzoquinonetreated mice. In addition, cells from mice treated with various benzene metabolites were more responsive to combinations of LPS and GM-CSF or M-CSF (23).…”

Protective effect of 1,2,4-benzenetriol on LPS-induced NO production by BV2 microglial cells

“…In addition, BQ and BT elicit histological injuries in liver, thymus, spleen, kidney and peripheral lymph nodes [13]. Treatment of mice with benzene (800 mg/kg), or HQ (100 mg/ kg), BT (25 mg/kg), or BQ (2 mg/kg) for 3 days, at doses that impair hematopoiesis, sensitize bone marrow leukocytes to produce increased amounts of NO in response to lipopolysaccharides (LPS) and interferon-c (IFN-c) [14]. They also increase the sensitivity of the cells to both granulocytemacrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) in the enhancement of NO production [14].…”

“…Treatment of mice with benzene (800 mg/kg), or HQ (100 mg/ kg), BT (25 mg/kg), or BQ (2 mg/kg) for 3 days, at doses that impair hematopoiesis, sensitize bone marrow leukocytes to produce increased amounts of NO in response to lipopolysaccharides (LPS) and interferon-c (IFN-c) [14]. They also increase the sensitivity of the cells to both granulocytemacrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) in the enhancement of NO production [14]. NO and inflammatory mediators, such as tumor necrosis factor-a (TNF-a) released from LPSactivated microglia can damage dopaminergic neurons [15].…”

“…Therefore, the enhanced cell growth and GM-CSF-induced colony formation or inhibited cell differentiation and apoptosis by BT treatment could be beneficial or harmful to the cells under stress [11][12][13][14]. Since BT is structurally related with sesamol, we examined whether BT had the neuroprotective effect on the activated microglia BV-2 cells under LPS or oxidative stress and on the ischemic rat brains.…”