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, terbinafine, 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.
Hankins
Eleanor G
EG
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Gillespie
John R
JR
Aikenhead
Kendra
K
Buckner
Frederick S
FS
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015870:Gene Expression; D000960:Hypolipidemic Agents / Q000494:pharmacology; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors; D007654:Ketoconazole / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000096:biosynthesis*; D000077291:Terbinafine; D014349:Trypanosoma cruzi / Q000201:enzymology* / Q000378:metabolism
D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D009025:Morpholines; D009281:Naphthalenes; D013261:Sterols; C015554:tridemorph; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D013186:Farnesyl-Diphosphate Farnesyltransferase; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D000077291:Terbinafine; D007654:Ketoconazole