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Glutathione protects macrophages and Leishmania major against nitric oxide-mediated cytotoxicity

Published online by Cambridge University Press:  01 June 1999

P. R. T. ROMÃO
Affiliation:
Faculty of Medicine of Ribeirão Preto, Department of Immunology, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil
S. G. FONSECA
Affiliation:
Faculty of Medicine of Ribeirão Preto, Department of Immunology, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil
J. S. HOTHERSALL
Affiliation:
Centre for Nephrology, Department of Medicine, The Institute of Urology and Nephrology, University College London, London, UK
A. A. NORONHA-DUTRA
Affiliation:
Centre for Nephrology, Department of Medicine, The Institute of Urology and Nephrology, University College London, London, UK
S. H. FERREIRA
Affiliation:
Department of Pharmacology, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil
F. Q. CUNHA
Affiliation:
Department of Pharmacology, University of São Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirão Preto, SP, Brazil

Abstract

The aim of this investigation was to examine whether macrophage and Leishmania major glutathione were involved in either host or parasite protection against NO cytotoxicity. Buthionine sulfoximine (BSO), an inhibitor of γ-glutamyl-cysteine synthase, caused a complete and irreversible depletion of macrophage glutathione, but only a 20% and reversible decrease in L. major glutathione. Glutathione-depleted macrophages, when activated with IFN-γ/LPS, released less than 60% of the NO produced by untreated macrophages, resulting in a corresponding decrease in their leishmanicidal activity. BSO-treated macrophages were more susceptible to the cytotoxic effects of the NO donor SNAP. Treatment of macrophages with 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase and trypanothione reductase or with Br-Octane, a glutathione-S-transferase substrate, resulted in a transient decrease in glutathione levels and did not increase the susceptibility of the macrophages to SNAP. Treatment of the promastigote forms of L. major with BCNU resulted in an 80% decrease in total glutathione concentration with no concomitant change in viability. However, this treatment rendered the parasites more susceptible to SNAP. Finally, macrophage glutathione protected the internalized L. major from SNAP. Overall, these results demonstrate that glutathione is an essential protective component against NO cytotoxicity on both macrophages and parasites.

Type
Research Article
Copyright
1999 Cambridge University Press

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