The objective of this competing continuation application is to delineate the structure activity relationships and mechanisms of activation leading to tumorigenesis by nitrofluorenes and nitro-9-fluorenones. These environmental pollutants cause mammary tumors in rats. The hypothesis to be tested is that tumorigenic potency depends on metabolic activation, which is in turn determined by the position of nitro groups and oxidation status of C9 of the fluorene. Activation is proposed to occur by a combination of nitro reduction and hydroxylamine activation, free radicals from redox cycling of nitroso and nitrofluorenes, and sulfation of C9-hydroxyl groups.
The specific aims are: 1) To evaluate the relative potencies of nitrofluorenes and their 9-hydroxy and 9-oxo derivatives following intramammary administration to rats in vivo. 2) To evaluate the capacity of rat mammary adipocyte and epithelial/stromal tissues to activate nitrofluorenes by one or two electron reductions in vitro. Reactivity of putative intermediates with deoxynucleosides in solution will be characterized, as will the capacity of redox intermediates to generate oxygen free radicals and initiate lipid peroxidation. 3) To determine the capacity of rat mammary microsomes to bioactivate fluorenes by C-9 hydroxylation, to determine the mutagenicity of C9-oxidized fluorenes in Salmonella typhimurium and to investigate the bioactivation of C9-oxidized fluorenes by rat liver sulfotransferases. 4) To identify DNA adducts formed in vivo from the bioactivation of nitrofluorenes, C9-oxidized fluorenes, and lipid peroxidation-derived malondialdehyde following intramammary instillation of the test compounds.
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