Quantitative structure–activity relationships in enzymatic single-electron reduction of nitroaromatic explosives: implications for their cytotoxicity

• Published in: Biochimica et biophysica acta Vol. 1528; no. 1; pp. 31 - 38
• Main Authors: Č≐nas, Narimantas, Nemeikait≐-Č≐nien≐, Aušra, Sergedien≐, Egl≐, Nivinskas, Henrikas, Anusevičius, Žilvinas, Šarlauskas, Jonas
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 03.09.2001
• Subjects: Aniline Compounds - chemistry; Aniline Compounds - toxicity; Animals; Cell Line, Transformed; Cytotoxicity; DT-diaphorase; Ferredoxin-NADP Reductase - chemistry; Ferredoxin:NADP + reductase; Kinetics; Models, Chemical; Molecular Structure; NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors; NAD(P)H Dehydrogenase (Quinone) - chemistry; NADPH-Ferrihemoprotein Reductase - chemistry; NADPH:cytochrome P-450 reductase; Nitrobenzenes - chemistry; Nitrobenzenes - toxicity; Oxidation-Reduction; Oxidative Stress; Pentryl; Quantitative Structure-Activity Relationship; Quantum Theory; Redox cycling; Sheep; Tetryl; TNT; Trinitrotoluene - chemistry; Trinitrotoluene - toxicity; Redox cycling; Cytotoxicity; FNR, ferredoxin:NADP + reductase; P, octanol/water partition coefficient; TNT, 2,4,6-trinitrotoluene; Ferredoxin:NADP + reductase; NADPH:cytochrome P-450 reductase; k cat, catalytic constant; cL 50, compound concentration for survival of 50% cells; TNC, 1,3,6,8-tetranitrocarbazole; E 7 1, single-electron reduction potential; Pentryl; ΔHf, enthalpy of reaction; TNT; DT-diaphorase; Tetryl; k cat/ K m, bimolecular rate constant; P-450R, NADPH:cytochrome P-450 reductase
• DOI: 10.1016/S0304-4165(01)00169-6
• ISSN: 0304-4165; 0006-3002

The mechanisms of cytotoxicity of polynitroaromatic explosives, an important group of environmental pollutants, remain insufficiently studied so far. We have found that the rate constants of single-electron enzymatic reduction, and the enthalpies of single-electron reduction of nitroaromatic compounds (ΔHf(ArNO 2 −⋅)), obtained by quantum mechanical calculation, may serve as useful tools for the analysis of cytotoxicity of nitroaromatic explosives with respect to the possible involvement of oxidative stress. The single-electron reduction rate constants of a number of explosives including 2,4,6-trinitrotoluene (TNT) and 2,4,6-trinitrophenyl- N-methylnitramine (tetryl), and model nitroaromatic compounds by ferredoxin:NADP + reductase (FNR, EC 1.18.1.2) and NADPH:cytochrome P-450 reductase (P-450R, EC 1.6.2.4) increased with a decrease in ΔHf(ArNO 2 −⋅). This indicates that the reduction rates are determined by the electron transfer energetics, but not by the particular structure of the explosives. The cytotoxicity of explosives to bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK) increased with a corresponding increase in their reduction rate constant by P-450R and FNR, or with a decrease in their ΔHf(ArNO 2 −⋅). This points to an importance of oxidative stress in the toxicity of explosives in this cell line, which was further evidenced by the protective effects of desferrioxamine and the antioxidant N, N′-diphenyl- p-phenylene diamine, and an increase in lipid peroxidation. DT-diaphorase (EC 1.6.99.2) exerted a minor and equivocal role in the cytotoxicity of explosives to FLK cells.