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Saperconazol: Ein hochspezifischer Inhibitor der Cytochrom P‐450‐abhängigen Ergosterin‐Synthese in Candida albicans, Aspergillus fumigatus und Trichophyton mentagrophytes
Author(s) -
Vanden Bossche H.,
Marichal P.,
Willemsens G.,
Bellens D.,
Gorrens J.,
Roels I.,
Coene M.-C.,
Le Jeune L.,
Janssen P. A. J.
Publication year - 1990
Publication title -
mycoses
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.13
H-Index - 69
eISSN - 1439-0507
pISSN - 0933-7407
DOI - 10.1111/myc.1990.33.7-8.335
Subject(s) - lanosterol , aspergillus fumigatus , candida albicans , ergosterol , biochemistry , chemistry , cryptococcus neoformans , cyp1a2 , demethylation , cytochrome , stereochemistry , ketoconazole , microsome , microbiology and biotechnology , biology , enzyme , sterol , cholesterol , antifungal , gene expression , gene , dna methylation
Summary The N‐1‐substituted triazole antifungal, saperconazole, is a potent inhibitor of ergosterol synthesis in Candida albicans, Aspergillus fumigatus and Trichophyton mentagrophytes . Fifty % inhibition is already achieved at nanomolar concentrations. The saperconazole‐induced inhibition of ergosterol synthesis coincides with an accumulation of 14‐methylated sterols, such as 24‐methylenedihydrolanosterol, lanosterol, obtusifoliol, 14 α ‐methylfecosterol, 14 α ‐methylergosta‐8,24(28)‐dien‐3, β ‐6 α ‐diol and 14 α ‐methylergosta‐5,7,22,24(28)‐tetraenol. This indicates that saperconazole interferes with the cytochrome P‐450 (P‐450)‐dependent 14 α ‐demethylation of lanosterol and/or 24‐methylenedihydrolanosterol. Saperconazole forms stable drug‐P‐450‐complexes by binding via its free triazole nitrogen to the heme iron and via its N‐1 substituent to the apoprotein moiety. The triazole derivative is a highly selective inhibitor of the 14 α ‐demethylase in fungal cells. It is a poor inhibitor of the 14 α ‐demethylation of lanosterol in rat and human liver cells. Saperconazole is, at concentrations as high as 10 µ M, devoid of effects on the P‐450‐dependent cholesterol side‐chain cleavage and 11 β ‐hydroxylase, 17,20‐lyase, 21‐hydroxylase and aromatase. Saperconazole does not interfere with the 2 α , 6 α ‐, 6 β ‐ and 7 α ‐hydroxylations of testosterone in microsomes from male rat liver. At high concentrations (> 5 µ M) an inhibition of the 16 β ‐+hydroxylations is seen.