Cytotoxicity of Nitroaromatic Explosives and their Biodegradation Products in Mice Splenocytes: Implications for their Immunotoxicity

Abstract

Nitroaromatic explosives like 2,4,6-trinitrotoluene (TNT) and 2,4,6-trinitrophenyl-Nmethyl- nitramine (tetryl) comprise an important group of toxic environmental pollutants, whose toxicity is mainly attributed to the flavoenzyme electrontransferase-catalyzed redox cycling of their free radicals (oxidative stress) and DT-diaphorase [NAD(P)H:quinone oxidoreductase, NQO1, EC 1. 6.99.2]-catalyzed formation of alkylating nitroso and/or hydroxylamine metabolites. Because of the incomprehensive data on the immunotoxic effects of nitroaromatic explosives, we have studied the structure-cytotoxicity relationships in the action of tetryl, TNT as well as its amino and hydroxylamino metabolites, and related nitroaromatic compounds towards mouse splenocyte cells. The protective effects of desferrioxamine and the antioxidant N,N′-diphenyl-p-phenylene diamine against the cytotoxicity of TNT and other nitroaromatics showed that the oxidative stress-type cytotoxicity mechanism takes place. In addition, the cytotoxicity of nitroaromatics is also partly prevented by an inhibitor of NQO1, dicumarol. The cytotoxicity of the amino metabolites of TNT is also partly prevented by α- naphthoflavone and isoniazide, which points to the involvement of cytochromes P-450 in their activation. In general the cytotoxicity of nitroaromatics in splenocytes increases with an increase in their single-electron reduction potential, Eζ . This points to the prevailing mechanism of the oxidative stress-type cytotoxicity. The obtained structure-activity relationship and the studies of other mammalian cell lines showed that the immunotoxic potential of nitroaromatic explosives may decrease in the order tetryl ≥TNT ≥ hydroxylamino metabolites of TNT > amino and diamino metabolites of TNT.

Nitroaromatic compounds: Environmental toxicity, carcinogenicity, mutagenicity, therapy and mechanism

“…Nitroaromatic explosives such as TNT and 2,4,6‐trinitrophenyl‐ N ‐methyl‐nitramine (tetryl) comprise an important group of toxic environmental pollutants whose toxicity is mainly attributed to the redox cycling of their free radicals (oxidative stress) and formation of nitroso and/or hydroxylamine metabolites (Miliukienė and Čėnas, ). In general, the cytotoxicity of nitroaromatics increases with an increase in their single electron reduction potential.…”

Species-specific differences in peroxisome proliferation, catalase, and SOD2 upregulation as well as toxicity in human, mouse, and rat hepatoma cells induced by the explosive and environmental pollutant 2,4,6-trinitrotoluene

“…We suggest that the toxicity of TNT is mainly exerted by oxidative stress and is determined by the cellular antioxidative capacity. Indeed, TNT releases hydrogen peroxide in rat (Kiria‐Sakai et al, ; Homma‐Takeda et al, ), bovine (Sarlauskas et al, ), mouse (Miliukiene and Cenas, ) and even bacteria (Berthe‐Corti et al, ; Zaripov et al, ; Naumenko et al, ), and antioxidants prevented cytotoxicity of TNT in lamb kidney fibroblasts (Sarlauskas et al, ). Moreover, an early metabolite of TNT, namely 4‐hydroxylamino‐2,6‐dinitrotoluene, was discovered as the main source of nitro radical anion (NО 2 •– ) and a superoxide radical anion (О 2 •– ) under aerobic conditions (Kumagai et al, ; Sarlauskas et al, ).…”

5-Vinylquinoline-substituted nitrofurans as inhibitors of trypanothione reductase and antitrypanosomal agents

“…Cell viability was assessed using the WST-1 reagent [21]. Primary murine splenocytes were prepared as previously described [22], resuspended at a concentration of 1.0 × 10 6 cells/ml in the RPMI 1640 medium with 5% FCS and antibiotics, and incubated for 24 h at 37°C in the humidified atmosphere containing 5% CO 2 in the absence or presence of compounds. The final content of DMSO in the medium, 0.6%, did not affect the cell viability.…”