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.

Abstract

The role of cell-specific metabolism in benzene toxicity was examined in both murine and human bone marrow. Hemopoietic progenitor cells and stromal cells are important control points for regulation of hemopoiesis. We show that the selective toxicity of hydroquinone at the level of the macrophage in murine bone marrow stroma may be explained by a high peroxidase/nicotanimide adenine dinucleotide phosphate, reduced [NAD(P)H]:quinone oxidoreductase (NQO1) ratio. Peroxidases metabolize hydroquinone to the reactive 1,4-benzoquinone, whereas NQO1 reduces the quinones formed, resulting in detoxification. Peroxidase and NQO1 activity in human stromal cultures vary as a function of time in culture, with peroxidase activity decreasing and NQO1 activity increasing with time. Peroxidase activity and, more specifically, myeloperoxidase, which had previously been considered to be expressed at the promyelocyte level, was detected in murine lineage-negative and human CD34+ progenitor cells. This provides a metabolic mechanism whereby phenolic metabolites of benzene can be bioactivated in progenitor cells, which are considered initial target cells for the development of leukemias. Consequences of a high peroxidase/NQO1 ratio in HL-60 cells were shown to include hydroquinone-induced apoptosis. Hydroquinone can also inhibit proteases known to play a role in induction of apoptosis, suggesting that it may be able to inhibit apoptosis induced by other stimuli. Modulation of apoptosis may lead to aberrant hemopoiesis and neoplastic progression. This enzyme-directed approach has identified target cells of the phenolic metabolites of benzene in bone marrow and provided a metabolic basis for benzene-induced toxicity at the level of the progenitor cell in both murine and human bone marrow.

Polymorphisms in Cytokine and Cellular Adhesion Molecule Genes and Susceptibility to Hematotoxicity among Workers Exposed to Benzene

“…Benzene can directly damage hematopoietic progenitor cells (5)(6)(7)(8)26), which could lead to apoptosis or decreased responsiveness to cytokines and cellular adhesion molecules. Alternatively, benzene toxicity to stromal cells or mature blood cells could disrupt the regulation of hematopoiesis, including hematopoietic commitment, maturation, or mobilization, through the network of cytokines, chemokines, and adhesion molecules (11)(12)(13)(14)27). Accordingly, hematotoxic effects could be enhanced among individuals exposed to benzene who have genetic variants that alter key pathways that regulate hematopoiesis.…”

“…Although there are ongoing concerns about its health effects (4), benzene continues to be used as a solvent in some countries, with several million workers exposed worldwide (4), and is a component of cigarette smoke, gasoline, crude oil, and automobile emissions (2). Several mechanisms have been suggested to account for benzeneinduced hematotoxicity, including (a) direct toxicity to hematopoietic progenitor cells by genotoxic and cytotoxic metabolites of benzene (5)(6)(7)(8) and (b) poisoning of the bone marrow stromal microenvironment (9,10), whereby shifts in regulatory molecules produced by marrow cells could disrupt normal hematopoiesis (11)(12)(13)(14).…”

Association of genetic polymorphisms in CYP2E1, MPO, NQO1, GSTM1, and GSTT1 genes with benzene poisoning.

“…Phenol is catalyzed by CYP2E1 to potentially toxic di-or trihydroxybenzenes such as hydroquinone, catechol, and 1,2,4-benzentriol (Eastmond et al 1987;Smith et al 1989;Subrahmanyam et al 1991). The di-or trihydroxy metabolites are further oxidized in the bone marrow by myeloperoxidase (MPO) to benzoquinones (Schattenberg et al 1994), a potent hematotoxic and genotic agent, which can be detoxified by NAD(P)H:quinone oxidoreductase 1 (NQO1) to less harmful hydroxybenzenes (Joseph et al 2000;Ross et al 1996). Thus we hypothesized that the deficient or altered activity of enzymes involved in benzene metabolism such as CYP2E1, MPO, NQO1, and GSTs would significantly affect susceptibility to benzene toxicity.…”

Induction of CYP4F3 by Benzene Metabolites in Human White Blood Cells in Vivo in Human Promyelocytic Leukemic Cell Lines and ex Vivo in Human Blood Neutrophils

“…Alternatively, metabolism of benzene and metabolites may occur in the marrow cells locally and contribute to its toxicity. For instance, production of semiquinones and quinones and subsequently oxidative stress via myeloperoxidase in bone marrow cells has been proposed (Ross et al, 1996). It has been posited that benzene metabolites rather than benzene itself mediate the multiple biological effects of benzene on the hematopoietic cells to give rise to bone marrow toxicity.…”