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
- Univ. of Colorado Health Sciences Center, Denver, CO (United States); and others
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/nicotanimicle 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{sup +} 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. 60 refs., 8 figs.
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 472157
- Report Number(s):
- CONF-9506288-; ISSN 0091-6765; CNN: Grant ES 04112; TRN: 97:001626-0009
- Journal Information:
- Environmental Health Perspectives, Vol. 104, Issue Suppl.6; Conference: Benzene `95: international conference on benzene toxicity, carcinogenesis, and epidemiology, Piscataway, NJ (United States), 17-20 Jun 1995; Other Information: PBD: Dec 1996
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
56 BIOLOGY AND MEDICINE
APPLIED STUDIES
55 BIOLOGY AND MEDICINE
BASIC STUDIES
BENZENE
METABOLISM
PEROXIDASES
ENZYME ACTIVITY
QUINONES
BIOLOGICAL EFFECTS
BONE MARROW
DETOXIFICATION
METABOLITES
TOXICITY
OCCUPATIONAL EXPOSURE
PETROLEUM REFINERIES
COMBUSTION PRODUCTS
UNLEADED GASOLINE
HEALTH HAZARDS
BIOASSAY