Beschreibung:
<jats:title>ABSTRACT</jats:title>
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Benznidazole (Bz), the drug used for treatment of Chagas' disease (caused by the protozoan
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Trypanosoma cruzi</jats:named-content>
), is activated by a parasitic NADH-dependent type I nitroreductase (NTR I). However, several studies have shown that other enzymes are involved. The aim of this study was to evaluate whether the aldo-keto reductase from
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">T. cruzi</jats:named-content>
(
<jats:italic>Tc</jats:italic>
AKR), a NADPH-dependent oxido-reductase previously described by our group, uses Bz as the substrate. We demonstrated that both recombinant and native
<jats:italic>Tc</jats:italic>
AKR enzymes reduce Bz by using NADPH, but not NADH, as a cofactor.
<jats:italic>Tc</jats:italic>
AKR-overexpressing epimastigotes showed higher NADPH-dependent Bz reductase activity and a 50% inhibitory concentration (IC
<jats:sub>50</jats:sub>
) value for Bz 1.8-fold higher than that of the controls, suggesting that
<jats:italic>Tc</jats:italic>
AKR is involved in Bz detoxification instead of activation. To understand the role of
<jats:italic>Tc</jats:italic>
AKR in Bz metabolism, we studied
<jats:italic>Tc</jats:italic>
AKR expression and NADPH/NADH-dependent Bz reductase activities in two
<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">T. cruzi</jats:named-content>
strains with differential susceptibility to Bz: CL Brener and Nicaragua. Taking into account the results obtained with
<jats:italic>Tc</jats:italic>
AKR-overexpressing epimastigotes, we expected the more resistant strain, Nicaragua, to have higher
<jats:italic>Tc</jats:italic>
AKR levels than CL Brener. However, the results were the opposite. CL Brener showed 2-fold higher
<jats:italic>Tc</jats:italic>
AKR expression and 5.7-fold higher NADPH-Bz reduction than the Nicaragua strain. In addition, NADH-dependent Bz reductase activity, characteristic of NTR I, was also higher in CL Brener than in Nicaragua. We conclude that although
<jats:italic>Tc</jats:italic>
AKR uses Bz as the substrate,
<jats:italic>Tc</jats:italic>
AKR activity is not a determinant of Bz resistance in wild-type strains and may be overcome by other enzymes involved in Bz activation, such as NADPH- and NADH-dependent reductases.
</jats:p>