Role of glutathione in the susceptibility of Trypanosoma cruzi to drugs

Moncada, Claudio; Repetto, Yolanda; Aldunate, J.; Letelier, María Eugenia; Morello, Antonio

doi:10.1016/0742-8413(89)90148-5

Cited by 23 publications

(16 citation statements)

References 19 publications

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“…In previous reports we showed evidence that correlates T(SH) 2 and GSH concentration with the susceptibility to nifurtimox and benznidazole of several T. cruzi strains (Moncada et al, 1989;Repetto et al, 1996;Maya et al, 1997). In this report, we found no direct evidence for the same role of MTs in T. cruzi (tables I and II).…”

Section: Discussionmentioning

confidence: 99%

“…The susceptibility of several T. cruzi strains and forms to nifurtimox and benznidazole correlate negatively with the intracellular free thiol (GSH and T(SH) 2 ) levels (Maya et al, 1997;Maya et al, 2001a). Buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, renders Trypanosoma cruzi parasites more susceptible to nifurtimox and benznidazole (Moncada et al, 1989;Repetto et al, 1996;Maya et al, 1997). The significant decrease in the GSH and T(SH) 2 concentration caused by conjugation with nifurtimox and benznidazole nitroreductive metabolites could explain the toxic effects of both drugs (Maya et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Effects of buthionine sulfoximine nifurtimox and benznidazole upon trypanothione and metallothionein proteins in Trypanosoma cruzi.

Maya

Rodríguez²,

Pino

et al. 2004

Biol. Res.

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Proteins rich in sulfhydryl groups, such as metallothionein, are present in several strains of the parasite Trypanosoma cruzi, the etiological agent of Chagas' disease. Metallothionein-like protein concentrations ranged from 5.1 to 13.2 pmol/mg protein depending on the parasite strain and growth phase. Nifurtimox and benznidazole, used in the treatment of Chagas' disease, decreased metallothionein activity by approximately 70%. T. cruzi metallothionein was induced by ZnCl 2 . Metallothionein from T. cruzi was partially purified and its monobromobimane derivative showed a molecular weight of approximately 10,000 Da by SDS-PAGE analysis. The concentration of trypanothione, the major glutathione conjugate in T. cruzi, ranged from 3.8 to 10.8 nmol/mg protein, depending on the culture phase. The addition of buthionine sulfoximine to the protozoal culture considerably reduced the concentration of trypanothione and had no effect upon the metallothionein concentration. The possible contribution of metallothionein-like proteins to drug resistance in T. cruzi is discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of buthionine sulfoximine nifurtimox and benznidazole upon trypanothione and metallothionein proteins in Trypanosoma cruzi.

Maya

Rodríguez²,

Pino

et al. 2004

Biol. Res.

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“…GSH synthesis has not been extensively 259 studied in T. cruzi but BSO has been used as an experimental tool for 260 decreasing GSH and, to a lesser extent, T(SH) 2 and Gsp levels 261 [43,44,53].…”

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confidence: 99%

Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification

Irigoı́n

Cibils

Comini

et al. 2008

Free Radical Biology and Medicine

133

101

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“…When added to cell cultures 24 h prior to evaluation of IC 50 s, BSO enhanced the susceptibilities of both wild-type and megazol-resistant trypanosomes to megazol. At 10 and 20 M, respectively, BSO caused the IC 50 for wild-type procyclics to drop from 0.28 to 0.14 Ϯ 0.02 M and that for resistant cells to drop from 29.24 to 7.33 Ϯ 0.56 M. With bloodstream forms, the IC 50 for wild-type cells shifted from 0.15 to 0.07 Ϯ 0.01 M while that for resistant cells shifted from 3.2 to 1.03 Ϯ 0.03 M. The concentration of BSO could not exceed 20 M since BSO is highly toxic to T. brucei (IC 50 s were 15.15 Ϯ 0.22 M and 11 Ϯ 0.39 M for procyclic and bloodstream forms, respectively), although related parasitic trypanosomatids T. cruzi (26) and Leishmania (19) can tolerate doses of BSO of 1 mM. The BSO effect was greater in resistant than in wild-type T. brucei.…”

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confidence: 99%

Activity of Megazol, a Trypanocidal Nitroimidazole, Is Associated with DNA Damage

Enanga

Ariyanayagam

Stewart

et al. 2003

Antimicrob Agents Chemother

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DNA damage associated with the trypanocidal activity of megazol [2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole] was shown in experiments in which DNA repair-deficient RAD51؊/؊ Trypanosoma brucei mutants were found to be hypersensitive to the drug. Parasites resistant to megazol were selected and showed modest cross-resistance to other trypanocides, although neither drug efflux nor changes to intracellular thiols correlated with resistance.New drugs are urgently required for treatment of human African trypanosomiasis (22). One compound with promise is megazol (5, 12, 13, 18), a nitroheterocyclic compound that forms a nitro radical anion upon reduction (31). Megazol appears to enter Trypanosoma brucei via passive diffusion (3), but little is known about its mode of action. We determined the effect of megazol in assays that measured oxidative and reductive stress. We also selected parasites resistant to megazol in order to assess cellular changes associated with resistance.Bloodstream forms (17) and procyclic forms (6) of T. brucei brucei (strain 427) were cultivated by using standard techniques. Assays measuring drug sensitivity were carried out to determine the drug concentration producing a 50% decrease in cell proliferation (IC 50 ) and the resistance factor (average ratio of the IC 50 for a resistant clone to the IC 50 for a wild-type clone). The Alamar Blue test (28) was used for bloodstream forms, while cell counting by using an improved Neubauer chamber was required for procyclics. For procyclic cells the IC 50 of megazol was 0.28 Ϯ 0.01 M, and for bloodstream forms the IC 50 was 0.15 Ϯ 0.02 M.To induce megazol resistance in vitro, trypanosomes were exposed to drug concentrations that doubled every 2 weeks, starting at 0.008 and 0.01 M for bloodstream forms and procyclics, respectively. After 6 months of cultivation, procyclic and bloodstream forms that tolerated 10 and 1 M megazol, respectively, were cloned by limiting dilution.The IC 50 for the cloned, resistant, procyclic line was 29.24 Ϯ 3.2 M (105-fold-reduced sensitivity), while the IC 50 for the bloodstream form line was 3.2 Ϯ 0.48 M (21-fold-reduced sensitivity).Cross-resistance to megazol and other trypanocides was also studied (Table 1). Moderate levels of cross-resistance to two nitroheterocyclic trypanocides, the nitrofuran nifurtimox and the nitroimidazole benznidazole, were detected. Significant, albeit low-level, cross-resistance to the melaminophenyl arsenical compounds cymelarsan, melarsen oxide, and melarsoprol, the diamidine compounds pentamidine and berenil, and suramin was also observed.Verapamil (20), PAK-104P (7), and two phenothiazine derivatives (prochlorperazine and trifluoperazine) (14) all inhibit cellular extrusion pumps but, when used at 5 M, failed to reverse megazol resistance in T. brucei. Efflux pumps are thus unlikely to play a significant role in the megazol resistance characterized here.It was recently shown that megazol exposure reduces trypanothione levels in Trypanosoma cruzi (23). Bloodstream form T. b...

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Role of glutathione in the susceptibility of Trypanosoma cruzi to drugs

Cited by 23 publications

References 19 publications

Effects of buthionine sulfoximine nifurtimox and benznidazole upon trypanothione and metallothionein proteins in Trypanosoma cruzi.

Effects of buthionine sulfoximine nifurtimox and benznidazole upon trypanothione and metallothionein proteins in Trypanosoma cruzi.

Insights into the redox biology of Trypanosoma cruzi: Trypanothione metabolism and oxidant detoxification

Activity of Megazol, a Trypanocidal Nitroimidazole, Is Associated with DNA Damage

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