Analysis of target cell susceptibility as a basis for the development of a chemoprotective strategy against benzene-induced hematotoxicities.
A goal of our research is to identify biochemical factors that underlie the susceptibility of bone marrow cell populations to benzene metabolites so as to develop a mechanistically based chemoprotective strategy that may be used in susceptible humans exposed to benzene. By doing biochemical risk analysis of bone marrow stromal cells from mice and rats and the human myeloid cell lines, HL-60 and ML-1; and by using buthionine sulfoximine and dicumarol we have observed that the susceptibility of these cell populations to hydroquinone (HQ) correlates with their concentration of glutathione (GSH) and activity of quinone reductase (QR). Accordingly, the induction of QR and GSH by 1,2-dithiole-3-thione (D3T) in these cell populations has resulted in a significant protection against the following hydroquinone-mediated toxicities: inhibition of cell proliferation and viability; reduced ability of stromal cells to support myelopoiesis; and altered differentiated of ML-1 cells to monocytes/macrophages. Preliminary in vivo experiments indicate that feeding mice D3T results in an induction of QR in the bone marrow compartment such that stromal cells are more resistant to hydroquinone-induced cytotoxicity in vitro. Overall, these studies suggest that in addition to hepatic cytochrome P4502E1, bone marrow QR and GSH are factors that could determine an individual's relative susceptibility to the toxic effects of benzene.
Trush
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MA
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA. mtrush@phnet.sph.jhu.edu
Twerdok
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LE
Rembish
S J
SJ
Zhu
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H
Li
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D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D001854:Bone Marrow Cells; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004351:Drug Resistance; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051381:Rats; D013871:Thiones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
D006873:Hydroquinones; D013871:Thiones; D013876:Thiophenes; D019392:Cytochrome P-450 CYP2E1; D016660:NAD(P)H Dehydrogenase (Quinone); D005978:Glutathione; D001554:Benzene; C049325:1,2-dithiol-3-thione; C031927:hydroquinone