Glutathione and the redox control system trypanothione/trypanothione reductase are involved in the protection of Leishmania spp. against nitrosothiol-induced cytotoxicity

Author(s)

P.R.T. Romão ^[1] ; J. Tovar ^[2] ; S.G. Fonseca ^[3] ; R.H. Moraes ^[4] ; A.K. Cruz ^[5] ; J.S. Hothersall ^[6] ; A.A. Noronha-Dutra ^[7] ; S.H. Ferreira ^[8] ; F.Q. Cunha ^[9]

Affiliation

^[1] Universidade do Sul de Santa Catarina (UNISUL). Curso de Medicina. Laboratório de Imunoparasitologia - Brasil

^[2] Royal Holloway University of London. School of Biological Sciences - Ucrânia

^[3] Universidade de São Paulo. Faculdade de Medicina. Instituto do Coração - Brasil

^[4] Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Departamento de Farmacologia

^[5] Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos - Brasil

^[6] University College of London. The Institute of Urology and Nephrology - Ucrânia

^[7] University College of London. The Institute of Urology and Nephrology - Ucrânia

^[8] Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Departamento de Farmacologia

^[9] Universidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Departamento de Farmacologia

• Document type: Journal article
• Source: Brazilian Journal of Medical and Biological Research; v. 39, n. 3, p. 355-363, 2006-03-00.

Abstract

Glutathione is the major intracellular antioxidant thiol protecting mammalian cells against oxidative stress induced by oxygen- and nitrogen-derived reactive species. In trypanosomes and leishmanias, trypanothione plays a central role in parasite protection against mammalian host defence systems by recycling trypanothione disulphide by the enzyme trypanothione reductase. Although Kinetoplastida parasites lack glutathione reductase, they maintain significant levels of glutathione. The aim of this study was to use Leishmania donovani trypanothione reductase gene mutant clones and different Leishmania species to examine the role of these two individual thiol systems in the protection mechanism against S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a nitrogen-derived reactive species donor. We found that the resistance to SNAP of different species of Leishmania was inversely correlated with their glutathione concentration but not with their total low-molecular weight thiol content (about 0.18 nmol/10(7) parasites, regardless Leishmania species). The glutathione concentration in L. amazonensis, L. donovani, L. major, and L. braziliensis were 0.12, 0.10, 0.08, and 0.04 nmol/10(7) parasites, respectively. L. amazonensis, that have a higher level of glutathione, were less susceptible to SNAP (30 and 100 µM). The IC50 values of SNAP determined to L. amazonensis, L. donovani, L. major, and L. braziliensis were 207.8, 188.5, 160.9, and 83 µM, respectively. We also observed that L. donovani mutants carrying only one trypanothione reductase allele had a decreased capacity to survive (~40%) in the presence of SNAP (30-150 µM). In conclusion, the present data suggest that both antioxidant systems, glutathione and trypanothione/trypanothione reductase, participate in protection of Leishmania against the toxic effect of nitrogen-derived reactive species. (AU)