title: 1,4-Diamino-2-butanone, a putrescine analogue, promotes redox imbalance in Trypanosoma cruzi and mammalian cells.
abstract: The putrescine analogue 1,4-diamino-2-butanone (DAB) is highly toxic to various microorganisms, including Trypanosoma cruzi. Similar to other α-aminocarbonyl metabolites, DAB exhibits pro-oxidant properties. DAB undergoes metal-catalyzed oxidation yielding H(2)O(2), NH(4)(+) ion, and a highly toxic α-oxoaldehyde. In vitro, DAB decreases mammalian cell viability associated with changes in redox balance. Here, we aim to clarify the DAB pro-oxidant effects on trypomastigotes and on intracellular T. cruzi amastigotes. DAB (0.05-5 mM) exposure in trypomastigotes, the infective stage of T. cruzi, leads to a decline in parasite viability (IC(50)c.a. 0.2 mM DAB; 4 h incubation), changes in morphology, thiol redox imbalance, and increased TcSOD activity. Medium supplementation with catalase (2.5 μM) protects trypomastigotes against DAB toxicity, while host cell invasion by trypomastigotes is hampered by DAB. Additionally, intracellular amastigotes are susceptible to DAB toxicity. Furthermore, pre-treatment with 100-500 μM buthionine sulfoximine (BSO) of LLC-MK2 potentiates DAB cytotoxicity, whereas 5 mM N-acetyl-cysteine (NAC) protects cells from oxidative stress. Together, these data support the hypothesis that redox imbalance contributes to DAB cytotoxicity in both T. cruzi and mammalian host cells.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: Chrislaine O
authors.initials: CO
authors.lastname: Soares
authors.forename: Walter
authors.initials: W
authors.lastname: Colli
authors.forename: Etelvino J H
authors.initials: EJ
authors.lastname: Bechara
authors.forename: Maria Julia M
authors.initials: MJ
authors.lastname: Alves
mesh_terms: D000818:Animals; D002460:Cell Line; D008954:Models, Biological; D016877:Oxidants / Q000494:pharmacology* / Q000633:toxicity; D010084:Oxidation-Reduction; D015800:Protozoan Proteins / Q000378:metabolism; D011700:Putrescine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014344:Trypanocidal Agents / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity
chemical_list: D016877:Oxidants; D015800:Protozoan Proteins; D013438:Sulfhydryl Compounds; D014344:Trypanocidal Agents; C014458:1,4-diaminobutanone; D013482:Superoxide Dismutase; D011700:Putrescine