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Phenotype of recombinant Trypanosoma cruzi which overexpress elongation factor 1-γ: Possible involvement of EF-1γ GST-like domain in the resistance to clomipramine

Abstract:

In previous studies, molecular and immunological approaches have been used to characterize the Trypansosoma cruzi elongation factor 1γ (TcEF-1γ). A primary sequence homology search revealed that the TcEF-1γ N-terminal domain showed significant homology to glutathione 5-transferases (GSTs). Although studies have suggested the involvement of EF-1γ 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-1γ in order to gain insight into its biological function. The growth of parasites which overexpress TcEF-1γ 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-1γ 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-1γ GST conserved enymatic 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-1γ. They also raise a central question regarding the GST as target for chemotherapeutic drugs in cancer research. © 1997 Elsevier Science B.V.