Ultrastructural alterations in Trypanosoma (Schizotrypanum) cruzi induced by Delta(24(25)) sterol methyl transferase inhibitors and their combinations with ketoconazole.
We report the ultrastructural alterations induced on the proliferative stages of Trypanosoma cruzi, the causative agent of Chagas' disease, by two Delta(24(25)) sterol methyl transferase (24(25)-SMT) inhibitors, 22,26-azasterol and 24(R,S),25-epiminolanosterol. Both compounds are sterol biosynthesis inhibitors which had previously been shown to be potent growth inhibitors and whose effects are potentiated by the C14a demethylase inhibitor, ketoconazole. Epimastigotes treated with the minimal growth inhibitory concentration of 22,26-azasterol (10 microM) for 144 h, which were completely depleted of endogenous 4-desmethyl sterols and accumulated 24-desalkyl sterols, showed the appearance of electron-dense granules, mitochondrial swelling and intense vacuolization. At high concentration (> or = 30 microM) the sterol analog induced gross alterations in the organization of chromatin and rapid cell lysis. The treatment of epimastigotes with 24-(R,S),25-epiminolanosterol induced at low concentrations (1 microM) alterations similar to those observed with 22,26-azasterol but additionally modifications of the kinetoplast were observed. Higher concentrations (> or = 3 microM) induced total lysis. The combination of both sterol analogs with ketoconazole, at sub-optimal concentrations, induced the same alterations as 22,26-azasterol (10 microM) or epiminolanosterol (1 microM). The results confirm the conclusions of previous studies which indicated that one important cytotoxic effects of sterol biosynthesis inhibitors in this organism is the alteration of the parasite's mitochondrial system.
Vivas
J
J
Centro de Biología Celular, Instituto de Biología Experimental, Facultad de Ciencias, Universidad Central de Venezuela, Apartado 47 860, Los Chaguaramos, Caracas 1041, Venezuela.
Urbina
J A
JA
de Souza
W
W