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 (H202) ± 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 H202 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.

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

“…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 Time (min) Figure 5.…”

“…A particular characteristic of N-arylhydroxamic acids is their ability to induce tumors at the sites of application (27). Thus, multiple ip injections of an aqueous suspension of N-OH-2-FAA (cumulative dose of -0.5 mmole/rat) yielded approximately 62% peritoneal tumor incidence in male or female rats.…”

In vitro nephrotoxicity induced by propanil

“…The 3,4-DCA produced by propanil hydrolysis can also undergo oxidation at 6-position of the phenyl ring as well as N-oxidation to 3,4-dichlorophenylhydroxylamine (3,4-DCPHA). Although not reported in propanil biotransformation studies, N -hydroxypropanil is a putative metabolite of propanil, since aromatic amides can undergo N-oxidation leading to reactive metabolites (Mulder and Meerman, 1983; Malejka-Giganti and Ritter, 1994). …”

Molecular Interactions of Carcinogenic Aromatic Amines, 4-Aminobiphenyl and 4,4’-Diaminobiphenyl, with Lactoperoxidase – Insight to Breast Cancer

“…Thiocyanate (SCN), present naturally in the human and animal systems, acts as the most preferred substrate for LPO and is oxidized to OSCN, which subsequently acts as an oxidizing agent for bacteria (16). Besides antimicrobial properties, LPO has a role in breast carcinogenesis through activation of carcinogenic aromatic amines such as, benzidine, 2aminofluorene and others, resulting in the formation of metabolites which are highly reactive and bind to DNA covalently (17). Human LPO has also been reported to activate estrogen into stable quinine methides which bind to DNA and initiate breast cancer (18).…”