RESUMEN
Current therapeutic regimens with first-line antitubercular agents are associated with a high rate of adverse effects which can lead to therapeutic failure. Understanding the nature and the severity of these effects is important for treatment optimization. The aim of present study was to investigate pyrazinamide potential effects on male rats DNA fragmentation, amino acid composition of bone type I collagen, reproductive capability and their posterity antenatal and postnatal development. Wistar albino male rats (160-200 g b.w.) were divided into three groups: I--received pyrazinamide per os at a dose of 1000 mg/kg b.w./day, II--at a dose of 2000 mg/kg b.w./day, in both groups it was given for 60 days; III--control. After 60 days of the experiment, rats of the experimental (groups I and II) and control groups were mated with intact virgin females. The amino acids contents of male rat bone type I collagens were determined using amino acid analyzer, epididymis and testis DNA fragmentation--electrophoretically; posterity antenatal development indices and postnatal development--by standard procedures. The study of pyrazinamide effects (administered in different doses) on males bone type I collagen amino acid contents and testis DNA fragmentation demonstrated the presence of dose-dependent pyrazinamide-mediated quantitative and qualitative changes in male rat reproductive organs DNA and extracellular matrix proteins in comparison with control. Changes in nucleic acids and proteins structure were accompanied by alterations in processes of fertilization (with intact females), embryogenesis and by lowering of posterity survival.
Asunto(s)
Aminoácidos/metabolismo , Huesos/efectos de los fármacos , Colágeno Tipo I/metabolismo , Fragmentación del ADN/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Pirazinamida/toxicidad , Reproducción/efectos de los fármacos , Animales , Huesos/metabolismo , Femenino , Masculino , Embarazo , Ratas , Ratas WistarRESUMEN
Necessity of tuberculosis chemotherapy adverse effects minimization requires a comprehensive evaluation of the effects of antitubercular drugs on reproductive system and extracellular matrix proteins. Wistar albino male rats (160-200 g) were divided into three groups: I--received pyrazinamide per os at a dose of 1000 mg/kg bw/day, II--at a dose of 2000 mg/kg bw/day, in both group it was given for 60 days; III--intact animals. The contents of amino acids in rat type I collagens were determined using an amino acid analyzer. Morphological analyses were carried out by an optical microscope. The study of the effects of pyrazinamide administered in different doses on type I collagen amino acid contents, testis cells morphologic and morphometric parameters and spermatogenesis demonstrated the presence of pyrazinamide-mediated quantitative and qualitative changes in male rat reproductive organs, spermatogenic epithelial cells and extracellular matrix proteins in comparison with norm.The largest number of changes were established at a dose 2000 mg/kg b.w./day. The observed collagen molecules changes could hence affect the properties and correct functioning of spermatogenic epithelium and other tissues of reproductive organs. They might be caused by pyrazinamide via cytochrome P450 2E1 induction, reactive oxygen species production or direct action of this compound on protein biosynthesis processes.