ANALYSIS OF TARGET-CELL SUSCEPTIBILITY AS A BASIS FOR THE DEVELOPMENTOF A CHEMOPROTECTIVE STRATEGY AGAINST BENZENE-INDUCED HEMATOTOXICITIES

A goal of our research is to identify biochemical factors that underli e the susceptibility of bone marrow cell populations to benzene metabo lites so as to develop a mechanistically based chemoprotective strateg y that may be used in susceptible humans exposed to benzene. By doing biochemical risk analysis of bone marrow stromal cells from mice and r ats and the human myeloid cell lines, HL-60 and ML-1; and by using but hionine sulfoximine and dicumarol we have observed that the susceptibi lity of these cell populations to hydroquinone (HQ) correlates with th eir concentration of glutathione (GSH) and activity of quinone reducta se (QR). Accordingly, the induction of QR and GSH by 1,2-dithiole-3-th ione (D3T) in these cell populations has resulted in a significant pro tection against the following hydroquinone-mediated toxicities: inhibi tion of cell proliferation and viability, reduced ability of stromal c ells to support myelopoiesis; and altered differentiation of ML-1 cell s to monocytes/macrophages. Preliminary in vivo experiments indicate t hat 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 fa ctors that could determine an individual's relative susceptibility to the toxic effects of benzene.