Upregulation of sterol C14-demethylase expression in Trypanosoma cruzi treated with sterol biosynthesis inhibitors

Infection with the protozoan, Trypanosoma cruzi, is the cause of Chagas disease that occurs widely throughout Latin America. T cruzi contains sterol biosynthesis enzymes, and produces sterol products similar to those found in fungi. Antifungal drugs that inhibit ergosterol biosynthesis have potent anti-T cruzi activity in vitro and in animal models. In this report, we describe the effects of sterol biosynthesis inhibitors (simvistatin, zaragosic acid, terbinatine, a lanosterol synthase inhibitor, ketoconazole, and tridemorph) on the regulation of two sterol biosynthesis genes and their protein products. Culturing T cruzi in the presence of the lanosterol synthase inhibitor, terbinafine, or ketoconazole increased mRNA levels of the sterol C14-demethylase gene approximately 7-12-fold. The sterol C14-demethylase protein levels were also elevated. The effects of the sterol biosynthesis inhibitors on hydroxymethylglutaryl-CoA reductase expression were minimal. Control of the upregulation of sterol C14-demethylase appears to be mediated through the 3'-untranslated region of the gene. The findings demonstrate that T cruzi can specifically regulate gene expression in response to derangements in its cellular functions. (c) 2005 Elsevier B.V. All rights reserved.