Interaction of Benznidazole Reactive Metabolites with Rat Liver Deoxyribonucleic Acid and Nuclear Proteins

Benznidazole (Bz) (N-benzyl-2-nitro-1-imidazole acetamide) is one of the drugs used in the chemotherapy of Chagas' disease. Microsomal suspensions anaerobically activated Bz in the presence or absence of NADPH to metabolites that covalently bind to proteins or to DNA incorporated into the incubation mixture. At high Bz concentrations (0.2 mM) NADPH enhanced the intensity of the process while at low Bz concentrations (0.02 mM) it decreased it. Nuclear preparations were also able to anaerobically activate Bz to reactive metabolites that bind covalently their DNA and proteins. The process was enzymatic and required NADPH. Most of the interaction between Bz metabolites and nuclear proteins involved the acidic non-histone proteins and those from the nuclear sap. A minor part of the interaction was with basic deoxyribonucleoproteins, acidic ribonucleoproteins and residual fractions. Almost no interaction with histones was observed. Potential toxicological implications of the observed interactions are analyzed.