| Environmental Health Issues Danuta Malejka-Giganti1,2 and Clare L. Ritter2 1Laboratory for Cancer Research, Veterans Affairs Medical
Center, Minneapolis, Minnesota; 2Department of Laboratory Medicine
and Pathology, University of Minnesota, Minneapolis, Minnesota Abstract
Peroxidative oxidations of chemical carcinogens including N-substituted aryl compounds could result in their metabolic activation because the products react with cellular molecules and lead to cytotoxicity, mutagenicity, and carcinogenicity. In vivo, peroxidative activities are chiefly of neutrophilic leukocyte origin. Neutrophils may be attracted to the site(s) of exposure to carcinogen and, via phagocytosis and respiratory burst, release oxidants that catalyze carcinogen activation and/or cause DNA damage. Our studies, presented herein, concern oxidations of carcinogenic N-arylhydroxamic acids, N-hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA) , and N-hydroxy-N-2-fluorenylbenzamide (N-OH-2-FBA) , by enzymatic and chemical systems simulating those of neutrophils, myeloperoxidase and hydrogen peroxide (H2O2) ± halide, and hypohalous acid and halide at the physiologic concentrations (0.1 M Cl- and/or 0.1 mM Br-) and the pH (4-6.5) of phagocytosis. Studies also concern oxidations of the hydroxamic acids by rat peritoneal neutrophils stimulated to undergo respiratory burst and release myeloperoxidase in medium-containing 0.14 M Cl- ± 0.1 mM Br-. The metabolites formed in the presence of exogenous H2O2 are consistent with two peroxidative mechanisms: one electron-oxidation to a radical that dismutates to equimolar 2-nitrosofluorene (2-NOF) and the ester of the respective hydroxamic acid and halide-dependent oxidative cleavage, especially efficient in the presence of Br-, to equimolar 2-NOF and the respective acyl moiety. 2-NOF and the esters undergo further enzymatic and nonenzymatic conversions to unreactive products and/or may bind to cellular macromolecules. The results suggest that peroxidative metabolism of N-arylhydroxamic acids by neutrophils, yielding the potent direct mutagen 2-NOF and the electrophilic esters, occurs in vivo and is involved in the activation and thus local tumorigenicities of the hydroxamic acids at the site(s) of application. -- Environ Health Perspect 102(Suppl 6) :75-81 (1994) Key words: N-arylamines, N-arylhydroxamic acids, N-hydroxy-N-2-fluorenylacetamide, N-hydroxy-N-2-fluorenylbenzamide, peroxidative metabolism, one-electron oxidation, halide-dependent oxidation, metabolism by neutrophils
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