The aims of this proposal are to investigate the relationship between the production of metabolites of benzene and the etiology of benzene-induced bone marrow depression and leukemia. The complete pathway of benzene metabolism will be investigated in CD-1, C57B1/6 and DBA/2 mice, Sprague Dawley rats and rabbits in vivo and in vitro using 3H and 14C-benzene. In addition to analyzing the formation of hydroxylated ring metabolites, we will seek ring opening products and carbon dioxide production from benzene. The different strains and species will be used because we have defined the differences in sensitivity to benzene by the rats and mice and now plan to explore the sensitivity of the rabbit. Metabolism in each of these models will be compared along with sensitivity. Studies are planned to explore the significance of covalently bound versus soluble metabolites and to related recovery from toxicity to persistence of both types of metabolites. We also plan to study the effects of benzene on nucleic acid metabolism in both mitochondria and nuclei. Having found that benzene inhibits mitochondrial RNA and protein synthesis while covalently binding to mitochondrial DNA, we plan to determine whether the same occurs in the nucleus. Of special interest was the finding that benzene appears to be metabolically activated in mitochondria. We plan to study the metabolism and the covalent binding in mitochondria of bone marrow which is the site of toxicity. Finally, we plan to investigate the mixed function oxidases in mitochondria and nuclei which are responsible for benzene metabolism.
Showing the most recent 10 out of 13 publications
