RESUMO
The α-aminoketone 1,4-diamino-2-butanone (DAB), a putrescine analogue, is highly toxic to various microorganisms, including Trypanosoma cruzi. However, little is known about the molecular mechanisms underlying DAB's cytotoxic properties. We report here that DAB (pK(a) 7.5 and 9.5) undergoes aerobic oxidation in phosphate buffer, pH 7.4, at 37°C, catalyzed by Fe(II) and Cu(II) ions yielding NH(4)(+) ion, H(2)O(2), and 4-amino-2-oxobutanal (oxoDAB). OxoDAB, like methylglyoxal and other α-oxoaldehydes, is expected to cause protein aggregation and nucleobase lesions. Propagation of DAB oxidation by superoxide radical was confirmed by the inhibitory effect of added SOD (50 U ml-1) and stimulatory effect of xanthine/xanthine oxidase, a source of superoxide radical. EPR spin trapping studies with 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) revealed an adduct attributable to DMPO-HO(â¢), and those with α-(4-pyridyl-1-oxide)-N-tert-butylnitrone or 3,5-dibromo-4-nitrosobenzenesulfonic acid, a six-line adduct assignable to a DAB(â¢) resonant enoyl radical adduct. Added horse spleen ferritin (HoSF) and bovine apo-transferrin underwent oxidative changes in tryptophan residues in the presence of 1.0-10 mM DAB. Iron release from HoSF was observed as well. Assays performed with fluorescein-encapsulated liposomes of cardiolipin and phosphatidylcholine (20:80) incubated with DAB resulted in extensive lipid peroxidation and consequent vesicle permeabilization. DAB (0-10 mM) administration to cultured LLC-MK2 epithelial cells caused a decline in cell viability, which was inhibited by preaddition of either catalase (4.5 µM) or aminoguanidine (25 mM). Our findings support the hypothesis that DAB toxicity to several pathogenic microorganisms previously described may involve not only reported inhibition of polyamine metabolism but also DAB pro-oxidant activity.
Assuntos
Sobrevivência Celular/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Putrescina/análogos & derivados , Espécies Reativas de Oxigênio/química , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Linhagem Celular , Ferritinas/efeitos dos fármacos , Radicais Livres/análise , Radicais Livres/toxicidade , Haplorrinos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Metais/química , Consumo de Oxigênio/efeitos dos fármacos , Poliaminas/química , Putrescina/química , Putrescina/farmacologia , Superóxidos/química , Superóxidos/metabolismo , Transferrina/efeitos dos fármacosRESUMO
This study was carried out to evaluate the iron status of 30 children aged 1 to 18 years who had been receiving total parenteral nutrition (TPN) for an average of 43 months with iron intakes of 100 micrograms/kg per day. Iron status was assessed by assaying the serum iron and ferritin levels and the transferrin saturation coefficient as a function of iron intake. Liver biopsy specimens were taken from 13 children. Twelve children had serum ferritin levels greater than 300 ng/ml, and 8 had levels greater than 800 ng/ml. The serum ferritin level and the transferrin saturation coefficient were positively correlated (r = 0.81; p < 0.01). The serum ferritin level was positively correlated with TPN duration and with the total iron intake (r = 0.68; p < 0.01). Of the 13 liver biopsy specimens, six showed signs of iron deposition. We conclude that there is a risk of iron overload in children receiving 100 micrograms iron per kilogram of body weight per day by TPN, indicating that intake should be reduced.
Assuntos
Alanina Transaminase/efeitos dos fármacos , Ferritinas/efeitos dos fármacos , Ferro/farmacologia , Fígado/efeitos dos fármacos , Nutrição Parenteral Total , Transferrina/efeitos dos fármacos , Adolescente , Alanina Transaminase/metabolismo , Biópsia , Criança , Pré-Escolar , Ferritinas/sangue , Humanos , Lactente , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Fatores de Tempo , Transferrina/metabolismoRESUMO
Se determina hierro sérico, capacidad total de fijación de hierro, capacidad latente de fijación de hierro y por ciento de saturación de la transferrina en 30 vegetarianos y en 18 no vegetarianos hombres y mujeres adultos. No se han encontrado diferencias estadísticamente significativas para los exámenes realizadas en vegetarianos. Sin embargo el reducido número de muestras realizadas no permite dar una conclusión definitiva.