Effects of ketoconazole on growth and sterol biosynthesis of Leishmania mexicana promastigotes in culture.
Ketoconazole, a clinically effective antimycotic agent active in vitro against the amastigote stage of Leishmania mexicana Walter Reed 227 in human monocyte-derived macrophages, was found to inhibit growth and impair sterol biosynthesis of the cultured promastigote stage by approx. 50% at a concentration of approx. 10(-8)M. Sterol biosynthesis was interfered with at the level of the removal of the 14 alpha-methyl group of lanosterol, as judged by changes in the distribution of [2-14C]mevalonate radioactivity among desmethyl sterol and methyl sterol thin-layer chromatography fractions, by the loss of 4-desmethyl sterols (mainly 5-dehydroepisterol), and by the accumulation of 14 alpha-methyl sterols. The growth inhibition and sterol changes were evident in promastigotes cultured in a cholesterol-rich medium and in a cholesterol-poor medium, even though promastigotes incorporated cholesterol. The mechanism of action of ketoconazole against promastigotes may be that postulated for Candida albicans: interference with membrane permeability secondary to loss of desmethyl sterols and accumulation of 14 alpha-methyl sterols.
D000818:Animals; D002855:Chromatography, Thin Layer; D003470:Culture Media; D005227:Fatty Acids / Q000096:biosynthesis; D007654:Ketoconazole / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013261:Sterols / Q000096:biosynthesis*
D003470:Culture Media; D005227:Fatty Acids; D013261:Sterols; D007654:Ketoconazole