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Perturbation of sterol biosynthesis by itraconazole and ketoconazole in Leishmania mexicana mexicana infected macrophages.

Abstract：

:The azole antifungals ketoconazole and itraconazole possess in vitro antileishmanial activity against Leishmania mexicana mexicana amastigotes in macrophages (cell line J774G8). As in yeast and fungi, the activity is likely to be due to inhibition of the cytochrome P-450-dependent 14 alpha-demethylation of lanosterol and/or 24,25-dihydrolanosterol. Indeed, 50% inhibition of ergosterol synthesis was observed at 0.21 microM ketoconazole and 0.15 microM itraconazole. At 5 microM ketoconazole, traces of ergosterol could be found, whereas no ergosterol could be detected in cells treated with 5 microM itraconazole. The inhibition of ergosterol biosynthesis was concomitant with an accumulation of the 14 alpha-methylsterols lanosterol and 24,25-dihydrolanosterol. Fifty percent inhibition of cholesterol synthesis in uninfected macrophages was achieved at 0.95 microM and 1.5 microM itraconazole and ketoconazole, respectively. In infected macrophages all [14C]acetate was incorporated in ergosterol, suggesting an inhibition in cholesterol synthesis in the host cells. An inhibition of ergosterol synthesis coincided with increasing cholesterol synthesis. The latter synthesis was inhibited at concentrations greater than 1 microM. However, even at 5 microM cholesterol synthesis was higher than under control conditions.

journal_name

Mol Biochem Parasitol

journal_title

Molecular and biochemical parasitology

authors

Hart DT,Lauwers WJ,Willemsens G,Vanden Bossche H,Opperdoes FR

doi

10.1016/0166-6851(89)90026-1

subject

Has Abstract

pub_date

1989-03-01 00:00:00

pages

123-34

issue

2

eissn

0166-6851

issn

1872-9428

pii

0166-6851(89)90026-1

journal_volume

33

pub_type

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