Peroxidative Metabolism of Carcinogenic N-Arylhydroxamic Acids: Implications for Tumorigenesis

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.

Reactive Nitrogen Oxygen Species Metabolize N-Acetylbenzidine

“…NO 2 • -like radicals are common intermediates shared by these nitrating reactions and are likely candidates for eliciting formation of the ABZ nitro product. Myeloperoxidase has been shown to metabolize a variety of aromatic amines, including ABZ, to reactive intermediates such as cation radicals ( − ). NO 2 • -like radicals may react with ABZ cation radicals forming 3‘-nitro-ABZ (Figure ).…”

Neutrophils and respiratory tract DNA damage and mutagenesis: a review

“…This is further supported by data showing that the protective effect of the MPO polymorphism was found to be strongest for small cell lung cancer specifically, which is a type of lung cancer strongly associated with cigarette smoking (151). Cigarette smoke is a potent source of chemical carcinogens and, at present, it is believed that the association between MPO and pulmonary carcinogenesis can be explained by the involvement of neutrophil-derived MPO in metabolic activation of inhaled chemical carcinogens, including aromatic amines (157)(158)(159) and heterocyclic amines (133). However, MPO activity has most frequently been linked to the metabolism of carcinogenic polycyclic aromatic hydrocarbons (PAHs) (126,(141)(142)(143)(144).…”

Peroxidative metabolism of carcinogenic N-arylhydroxamic acids: implications for tumorigenesis.

“…Formation of small amounts of 2-NO2F that was H202-dependent and both enzymatic and nonenzymatic, could not account for all the losses of 2-NOF. The low recoveries of the latter were likely because of reactivity with cellular components such as glutathione or protein binding or both (27). The recovery of N-AcG-2-FAA decreased from 75 to 8% in 24 min (34).…”

“…The determination of small amounts of the esters from oxidations of the hydroxamic acids by hypohalous acids indicated relatively low levels of le--oxidation. The ESR signal of nitroxyl-free radical, indicative of le--oxidation, was detected only during oxidation of N-OH-2-FAA by HOCI (Figure 2 The carcinogenicities for rat peritoneum of N-OH-2-FAA, and especially N-OH-2-FBA, administered ip in aqueous suspensions (27), suggested influx of leukocytes in response to the foreign compound deposits. Hence, neutrophils, the predominant leukocytes, were elicited into rat peritoneum through ip injections of proteose peptone and harvested within 4 hr for Environmental Health Perspectives In the absence of Ca++, azurophil granules containing MPO remained intact when the cells were treated with PMA to effect the respiratory burst.…”

“…Based on our studies, several approaches appear viable: a) demonstration of the presence of the more stable derivatives (e.g., 4-OH-2-FAA, 2-NO2F, o-BzO-2-FBA) ( Figure 1); b) characterization of both carcinogen-and oxidant-induced DNA damage in target tissues (e.g., peritoneal serosa); c) determination of the effect of increasing physiologic concentration of Br-, a significant environmental pollutant (36), on the tumorigenicity of the hydroxamic acids; and d) demonstration of the interaction products of the major metabolite 2-NOF with glutathione, protein, and unsaturated lipids. Because of the exceptional direct mutagenicity of 2-NOF in the bacterial systems (27), it especially merits investigation. Recent evidence that interaction of C-nitroso compounds with unsaturated lipids is a source of 0°- (37) or genotoxic 2 products via lipid peroxidation (38) may be pertinent to the biologic significance of 2-NOF.…”