Metabolism of the carcinogen N-hydroxy-N-2-fluorenylacetamide by rat peritoneal neutrophils.
The in vitro metabolism of a locally carcinogenic N-hydroxy-N-2-fluorenylacetamide (N-OH-2-FAA) by rat peritoneal polymorphonuclear leukocytes (PMNL), chiefly neutrophils, elicited with intraperitoneal injections of proteose peptone, was examined. At 10(6) PMNL/ml in media containing halide (X-), 0.14 M Cl- +/- 0.1 mM Br- (without Ca++ and Mg++), addition of 10 nM phorbol myristate acetate (PMA) resulted in generation of superoxide anion and H2O2. Subsequent cetyltrimethylammonium Cl- (Cetac) addition at 0.002% effected myeloperoxidase (MPO) activity release. PMNL treated with PMA and/or Cetac did not metabolize N-OH-2-FAA (30 microM). However, 1-2 pulses of H2O2 (50 microM) after Cetac addition resulted in oxidation of N-OH-2-FAA to N-acetoxy-2-FAA (< 0.5 microM) and 2-nitrosofluorene (2-NOF) (1-2 microM). In the presence of Br- 2-NOF was increased (3-5 microM). The results are consistent with oxidation of N-OH-2-FAA by MPO/H2O2 and MPO/H2O2/X- via two pathways: one electron oxidation leading to N-acetoxy-2-FAA and 2-NOF, and X(-)-dependent oxidation to 2-NOF. N-Acetoxy-2-FAA (10 microM) incubated with PMNL under similar conditions was converted non-enzymatically to 4-OH-2-FAA (< or = 5 microM) and enzymatically to N-OH-2-FAA (< or = 3 microM). In the presence of H2O2, smaller amounts of these products were formed. Formation of N-OH-2-FAA was prevented by paraoxon (0.1 mM) suggesting O-deacetylase activity. However, accountability for N-acetoxy-2-FAA decreased with time, presumably because of binding to cellular macromolecules. With H2O2 addition, 2-NOF (10 microM) was converted to 0.5 or 0.25 microM 2-nitrofluorene by active PMNL or heat-inactivated cell lysates, respectively. Low recoveries of 2-NOF were also attributed to binding. The results suggest that PMNL may be involved in activation of the carcinogenic N-arylhydroxamic acids in vivo.[1]References
- Metabolism of the carcinogen N-hydroxy-N-2-fluorenylacetamide by rat peritoneal neutrophils. Malejka-Giganti, D., Ritter, C.L., Willmott, L.D. Carcinogenesis (1993) [Pubmed]
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