In vitro and in vivo reduction of antimonyV drugs

The hypothesis that SbV agents act only as prodrugs, and that the reduction of SbV to Sb111 species in vivo is responsible for the actual mechanism of action was first proposed by Goodwin and Page after they found that a reduction of SbV occurred in the host organism.69,70 This hypothesis was supported by the observation that the SbIII contents in serum and urine samples of patients were 5-25% and 50%, respectively, after treatment with SbV drugs,71,72 and significant amounts of SbIII were detected in tissues and serum in L. garnhami-infected hamsters treated with meglumine antimonate.73 The reduction/activation hypothesis was further supported by the fact that IC50 of antimony chemotherapy is 60- to over 600-fold higher for promastigotes (the parasites culture at pH 7.4 and 298 K to resume the extracellular stage) than for amastigotes (the parasites culture at pH 5.0 and 310 K to resume the intracel-lular form) despite the intracellular antimony concentrations being similar at the respective IC50.74

Trivalent antimonials were generally more toxic than the pentavalent anti-monials for both promastigotes and intramacrophage amastigotes.75 78 It has been demonstrated that the extracellular amastigotes of L. infantum were most susceptible to Sb111.78 Macrophages can also retain both Sb111 and SbV from the medium up to 3 days during a 4 h exposure, and metabolic conversion of SbV to Sb111 was found inside the macrophage.79 In addition, axenic amastigotes of L. infantum were poorly susceptible to meglumine antimonate (SbV), in contrast to those growing inside human leukemia monocyte cell lines (THP-1 cells).79 Consistent with an observation that toxicity of SbV towards the parasitic protozoa indeed depends on the level of Sb111, a strong cross-resistance to meglumine antimonate was noticed in SbIII-resistant axenic L. infantum amastigotes growing in THP-1 cells.79 These results again suggest that fairly toxic SbV is converted in vivo into highly active SbIII compounds and the SbV reduction could take place at the host cells. However, the intracellular reduction of pentavalent antimony inside parasites was also possible since intracellular SbV reduction was apparent in amastigotes at a stage-specific manner in L. donovani.80

Recently, an in vitro experiment showed that up to 30% of the SbV was reduced to Sbra in amastigotes (310 K), while little reduction of SbV to Sbra was observed in promastigotes (299 K) after 12 h incubation.80 In spite of similar standard redox potentials between trypanothione (T(SH)2) and the tripeptide GSH (7-L-Glu-L-Cys-Gly, Figure 23.3) (E0 = -0.242 and -0.230 V, respectively),81 trypanothione can reduce sodium stibogluconate (SbV) within several hours, in contrast to its analogue, GSH (days). The reduction process is both pH- and temperature-dependent and proceeds more effectively at higher temperature and acidic pH, indicating that rapid reduction of SbV by T(SH)2 is favored in amastigotes.82 84 This suggests that trypanothione may play an important role in antimonial activation. T(SH)2 could therefore be important in the activation of SbV inside parasites, although the presence of an enzyme to reduce SbV cannot be excluded.

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