Metabolic activation of 2,4,6-trinitrotoluene; a case for ROS-induced cell damage

The explosive compound 2,4,6-trinitrotoluene (TNT) is well known as a major component of munitions. In addition to its potential carcinogenicity and mutagenicity in humans, recent reports have highlighted TNT toxicities in diverse organisms due to its occurrence in the environment. These toxic effects have been linked to the intracellular metabolism of TNT, which is generally characterised by redox cycling and the generation of noxious reactive molecules. The reactive intermediates formed, such as nitroso and hydroxylamine compounds, also interact with oxygen molecules and cellular components to cause macromolecular damage and oxidative stress. The current review aims to highlight the crucial role of TNT metabolism in mediating TNT toxicity, via increased generation of reactive oxygen species. Cellular proliferation of reactive species results in depletion of cellular antioxidant enzymes, DNA and protein adduct formation, and oxidative stress. While TNT toxicity is well known, its ability to induce oxidative stress, resulting from its reductive activation, suggests that some of its toxic effects may be caused by its reactive metabolites. Hence, further research on TNT metabolism is imperative to elucidate TNT-induced toxicities.