CELL-SPECIFIC ACTIVATION AND DETOXIFICATION OF BENZENE METABOLITES INMOUSE AND HUMAN BONE-MARROW - IDENTIFICATION OF TARGET-CELLS AND A POTENTIAL ROLE FOR MODULATION OF APOPTOSIS IN BENZENE TOXICITY

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 hemopoie sis. We shaw that the selective toxicity of hydroquinone at the level of the macrophage in murine bone marrow stroma may be explained by a h igh peroxidase/nicotanimide adenine dinucleotide phosphate, reduced [N AD(P)H]:quinone oxidoreductase (NQO1) ratio. Peroxidases metabolize hy droquinone to the reactive 1,4-benzoquinone, whereas NQO1 reduces the quinones formed, resulting in detoxification. Peroxidase and NQO1 acti vity 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, myetoperoxidase, whi ch had previously been considered to be expressed at the promyelocyte level, was detected in murine lineage-negative and human CD34(+) proge nitor cells. This provides a metabolic mechanism whereby phenolic meta bolites of benzene can be bioactivated in progenitor cells, which are considered initial target cells for the development of leukemias. Cons equences 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 t hat it may be able to inhibit apoptosis induced by other stimuli. Modu lation of apoptosis may lead to aberrant hemopoiesis and neoplastic pr ogression. This enzyme-directed approach has identified target cells o f the phenolic metabolites of benzene in bone marrow and provided a me tabolic basis for benzene-induced toxicity at the level of the progeni tor cell in both murine and human bone marrow.