Phenotype of recombinant Trypanosoma cruzi which overexpress elongation factor 1-gamma: possible involvement of EF-1gamma GST-like domain in the resistance to clomipramine.
In previous studies, molecular and immunological approaches have been used to characterize the Trypansosoma cruzi elongation factor 1gamma (TcEF-1gamma). A primary sequence homology search revealed that the TcEF-1gamma N-terminal domain showed significant homology to glutathione S-transferases (GSTs). Although studies have suggested the involvement of EF-1gamma in the protein synthesis machinery, the exact function of this protein, particularly the role of its GST-like domain, is not fully understood. Therefore, we have used the protozoan parasite T. cruzi, as a recipient for a shuttle vector which allows overexpression of TcEF-1gamma in order to gain insight into its biological function. The growth of parasites which overexpress TcEF-1gamma and control cells was equally sensitive to inhibition by nifurtimox and benznidazole, which exert a trypanocidal activity through the production of free radicals. In contrast, a strong resistance of transformed organisms to the tricyclic antidepressant drug, clomipramine, a lipophilic compound, was observed, whereas control cells were highly sensitive. Our findings suggest that TcEF-1gamma participates in the detoxification of lipophilic compounds probably by conjugation with glutathione through its GST-like domain. To our knowledge, this is the first report showing that the eukaryotic EF-1gamma GST conserved enzymatic model could play a role in drug resistance. Furthermore, these results reinforce the notion that the aggressiveness of certain tumours could in part be linked to overexpression of EF-1gamma. They also raise a central question regarding the GST as target for chemotherapeutic drugs in cancer research.
Billaut-Mulot
O
O
Institut Pasteur de Lille, France.
Fernandez-Gomez
R
R
Ouaissi
A
A
D000818:Animals; D002997:Clomipramine / Q000494:pharmacology*; D018076:DNA, Complementary / Q000235:genetics; D004351:Drug Resistance; D005982:Glutathione Transferase / Q000235:genetics*; D009547:Nifurtimox / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology; D020648:Peptide Elongation Factor 1; D010445:Peptide Elongation Factors / Q000235:genetics*; D010641:Phenotype; D014344:Trypanocidal Agents / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
D018076:DNA, Complementary; D009593:Nitroimidazoles; D020648:Peptide Elongation Factor 1; D010445:Peptide Elongation Factors; D014344:Trypanocidal Agents; D005982:Glutathione Transferase; D009547:Nifurtimox; D002997:Clomipramine; C009999:benzonidazole