Glutathione-induced conversion of pentavalent antimony to trivalent antimony in meglumine antimoniate

The standard treatment of human leishmaniases involves the use of pentavale nt antimony [Sb(V)] compounds, including meglumine antimoniate, The mode of action of these compounds has not been fully elucidated. The possibility t hat Sb(III) is involved has been suggested; however, the biomolecule that m ay induce the conversion of Sb(V) to Sb(III) has not yet been identified, I n the present study, we investigated both the ability of reduced glutathion e (GSH) to promote the reduction of Sb(V) into Sb(III) in meglumine antimon iate and the effects of pH and temperature on this transformation, GSH did promote the reduction of Sb(V) into Sb(III) in a dose-dependent manner. Whe n GSH and meglumine antimoniate were incubated together at a GSH/Sb molar r atio superior or equal to 5:1, all antimony was encountered in the reduced form, indicating a stoichiometry of 5:1 between GSH and Sb(V) in the reacti on. The reaction between Sb(V) and GSH was favored at an acidic pH (pH 5) a nd an elevated temperature (37 degreesC), conditions found within the phago lysosome, in which Leishmania resides. For instance, about 30% of the Sb(V) (concentration, 2mM) was converted to Sb(III) following incubation for 3 d ays with 10 mM I GSH at pH 5 and 37 degreesC, Our data support the hypothes is that Sb(V) would be converted by GSH, or a related thiol compound, to mo re toxic Sb(III) in the phagolysosome of macrophages.