Benznidazole-induced ultrastructural and biochemical alterations in rat colon

AIM: To study the effects of benznidazole (Bz), a drug used in the chemothe rapy of the acute and the intermediate phase of Chagas' disease, on the col on of rats. METHODS: Sprague Dawley male rats received Bz 100 mg/kg ig. Aft er 24 h colons were examined by electron microscopy. Concentrations of Bz i n colonic tissue were measured by HPLC. Bz nitroreduction was followed by t he decrease in the drug concentration using spectrophotometry and HPLC or b y covalent binding to proteins of reactive products formed under in vivo an d in vitro conditions. RESULTS: Colon mucosa of Bz-treated rats showed inte nse ultrastructural alterations: abundant mucus secretion at the level of t he Goblet cells and dilatation of the endoplasmic reticulum and the Golgi a pparatus in epithelial cells. The concentration of Bz in tissue was (59 +/- 18) and (93 +/- 14) nmol/g (protein) 1 and 3 h after oral administration t o rats, respectively. Colonic microsomes anaerobically activated Bz in the presence of NADPH. This activating nitroreductive pathway only involved a m inor part of the total Bz and could not be detected spectrophotometrically or by HPLC analysis of the Bz consumed. Reactive metabolites that bound cov alently to microsomal proteins were formed in this process. The covalent bi nding was also observed in vivo 1, 3, 6, and 24 h after administration of t he labeled drug to rats. CONCLUSION: Reactive Bz metabolites produced durin g nitroreductive bioactivation of the drug in the colonic mucosa could inte ract with proteins and other cellular constituents to cause injury.