Nitroimidazole Action in Entamoeba histolytica: A Central Role for Thioredoxin Reductase
Figure 6
Model of Metronidazole Activation and Metronidazole Action in E. histolytica
After uptake by the cell, metronidazole is reduced by thioredoxin reductase (TrxR) (as shown in this study; black arrow), possibly by purine nucleoside phosphorylase (hypothesized in this study; dotted arrow) and, probably, by ferredoxin (shown to reduce metronidazole in T. vaginalis and G. intestinalis; interrupted arrow). After activation, metronidazole can develop its toxicity in a 2-fold way, either as a nitroradical anion or, if further reduced, as a reactive nitrosoimidazole (red arrows). The nitroradical anion can reduce O2 and thereby generate reactive oxygen species, which are highly detrimental to the microaerophilic E. histolytica cell. Alternatively, the nitrosoimidazole is generated, which forms adducts with non-protein thiols and/or proteins, resulting in the depletion of non-protein thiols and the modification of thioredoxin reductase (TrxR), thioredoxin (Trx), superoxide dismutase (SOD), metronidazole target protein 1 (Mtp1), and purine nucleoside phosphorylase (PNP). Presumably, these five proteins become targets of modification due to their close spatial proximity to the site of metronidazole activation, i.e., thioredoxin reductase. The formation of covalent metronidazole adducts with proteins involved in antioxidant defense is likely to render the cells more vulnerable to oxidative stress, thereby exacerbating metronidazole toxicity to E. histolytica in the presence of oxygen [43].