RESUMO
Two nitroheterocyclic drugs, nifurtimox (NFX) and benznidazole (BZ), used in the treatment of Chagas' disease have serious side effects attributed to their nitroreduction to reactive metabolites. Here, we report that these drugs reach the mammary tissue and there they could undergo in situ bioactivation. Both were detected in mammary tissue from female Sprague-Dawley rats after their intragastric administration. Only NFX was biotransformed by pure xanthine-oxidoreductase and from tissue cytosol. These activities were purine dependent and were inhibited by allopurinol. Also, only NFX was biotransformed by microsomes in the presence of ß-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), and was inhibited by carbon monoxide and partially by diphenyleneiodonium. NFX treatment produced significant decrease in protein sulfhydryl content after 1, 3 and 6 hours; no increases in protein carbonyl content at any time tested and significantly higher levels of lipid hydroperoxides at 3 and 6 hours; besides, ultrastructural observations after 24 hours showed significant differences in epithelial cells compared to control. These findings indicate that NFX might be more deleterious to mammary tissue than BZ and could correlate with early reports on its ability to promote rat mammary tissue toxicity.
Assuntos
Glândulas Mamárias Animais/metabolismo , Nifurtimox/farmacocinética , Nitroimidazóis/farmacocinética , Tripanossomicidas/farmacocinética , Alopurinol/farmacologia , Animais , Fracionamento Celular , Cromatografia Líquida de Alta Pressão , Feminino , Peroxidação de Lipídeos/efeitos dos fármacos , Glândulas Mamárias Animais/química , Glândulas Mamárias Animais/ultraestrutura , Microscopia Eletrônica de Transmissão , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Nifurtimox/análise , Nifurtimox/metabolismo , Nitroimidazóis/análise , Nitroimidazóis/metabolismo , Nitrorredutases/metabolismo , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Compostos de Sulfidrila/análise , Compostos de Sulfidrila/metabolismo , Tripanossomicidas/análise , Tripanossomicidas/metabolismoRESUMO
Recent studies from our laboratory provided evidence that part of the carcinogenic effects of ethanol consumption might be related to its in situ metabolism at cytosolic and microsomal levels, to the mutagen acetaldehyde and to hydroxyl and 1-hydroxyethyl radicals. In this work, we report on our experiments where Sprague-Dawley female rats were exposed to the standard Lieber & De Carli diet for 28 days. We observed: the induction of the (xanthineoxidoreductase mediated) cytosolic and microsomal (lipoxygenase mediated) pathways of ethanol metabolism; promotion of oxidative stress as shown by increased formation of lipid hydroperoxides; delay in the t-butylhydroperoxide induced chemiluminiscence, and a significant decrease in protein sulfhydryls. In addition, the epithelial cells showed ultrastructural alterations consisting of markedly irregular nuclei, with frequent invaginations at the level of the nuclear envelope, condensation of chromatin around the inner nuclear membrane, and marked dilatation of the nuclear pores showing filamentous material exiting to the cytoplasm. In conclusion, the presence in mammary epithelial cells of cytosolic and microsomal pathways of ethanol bioactivation to carcinogenic and to tumorigenic metabolites might play a role in alcohol promotion of breast cancer.
