Résumé
Ketoconazole, a dioxolane imidazole, affects growth and sterol synthesis by Trypanosoma (Schizotryparum) cruzi epimastigotes in a time - and concentration - dependent manner. Starting with a cell density of 10 7 cells/ml, a 10 -4M concentration of the drug blocks instantaneously growth, but with 10 -5M and 10 -6M growth arrest takes place at 48 and 96 hours, respectively. A study of the sterol content of the parasites and their de novo synthesis reveals that the drug induces the accumulation of trimethyl- and, to a much lesser extent, dimethyl-sterols with a progressive decrease of ergosterol-like desmethyl-sterol pool. Sterols added to the growth medium can partially reverse the growth inhibitory effects of ketoconazole, ergosterol being much more effective that cholesterol in this action. These facts suggest an essential function performed in T cruzi by ergosterol, which cannot be replaced by cholesterol, a compound which is passively absorbed from the growth medium and remains in the drug-treated cells. At 10 -6M ketoconazole blocks completely the incorporation of 14C-acetate in desmethyl-sterols and >97% of the radioactivity appears in the trimethyl-sterol fraction at 24 hours; further incubation leads to the appearance of a slight amount of radioactivity in the dimethyl-sterol fraction (10% at 96 hours)..