Activation of Carcinogenic N-Arylhydroxamic Acids by Peroxidase/H2O2/Halide Systems: Route to C-Nitroso Aromatics
Evidence that locally carcinogenic N-arylhydroxamic acids may be activated by oxidants generated by leukocytes has been obtained from model systems including tissue peroxidases, myeloperoxidase (MPO)/H2O2/ halide (X-) or hypohalous acids (HOX). Peroxidative oxidations of N-hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA) via one electron (le-) to equimolar 2-nitrosofluorene (2-NOF) and N-acetoxy-2-FAA, and via oxidative cleavage to 2-NOF were determined. The latter oxidation predominated with peroxidase-rich extracts of rat uterus and mammary gland and with eosinophils from intraperitoneal fluid in the presence of H2O2, Br- and cationic detergent. Contribution to 2-NOF by le- oxidation was up to 50% at 0.1 mM Br- and pH 7.4, but negligible at 10 mM Br- and pH 5.5. Oxidation of N-OH-2-FAA by MPO of human neutrophils in the presence of physiologic concentrations of Cl- (0.1 M) or Br- (0.1 mM) or their mixture was examined in the pH range of 4 to 6.5. At the respective pH optima (4 for Br- and 5 for Cl- or Cl- + Br-), oxidation of N-OH-2-FAA to 2-NOF by MPO/H2O2 was much more rapid with Br- and Br- + Cl- than with C1-. Since HOBr oxidized N-OH-2-FAA to 2-NOF much more rapidly than did HOC1, MPO/H2O2-catalyzed oxidation in the presence of C1-+Br- was possibly due in part to HOBr. le- oxidation of N-OH-2-FAA occurred to a lesser extent in chemical (HOX) than enzymatic systems (MPO/H2O2/X-), in which it appeared to be stimulated by Br- at pH > 5.5. In the presence of taurine, a scavenger of hypohalous acids in vivo, oxidation of N-OH-2-FAA to 2-NOF bv MPO/H2O2 was unaffected with Br-, inhibited with Cl-, and partially inhibited with Cl- + Br-. These results were linked to N-halotaurine formation since it was found that N-bromotaurine, but not N-chloro-taurine, oxidized N-OH-2-FAA chiefly to 2-NOF. The possibility that 2-NOF through its interactions with unsaturated lipids may initiate lipid peroxidation was investigated by measurements of malondialdehyde (MDA), a lipid degradation product, following aerobic incubations of 2-NOF with arachidonic, linolenic or linoleic acid at a molar ratio of 1:1. The amounts of MDA were optimal after 4 hr and were increased by 50% when 2-NOF was preincubated with the fatty acids for 24 hr under anaerobic conditions. Our studies indicate potential significance of: 1) Br--derived oxidants in activation of carcinogenic N-arylhydroxamic acids to C-nitroso aromatics, and 2) interactions of C-nitroso aromatics with unsaturated lipids leading to lipid peroxidation and thus, genotoxicity.
KeywordsAldehyde Sarcoma Oleate Acetaminophen Bromine
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