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Ketoconazole (antifungal) inhibits CYP 450 - a requirement for some parasites
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Published: 11 years ago

Ketoconazole (antifungal) inhibits CYP 450 - a requirement for some parasites

Identification of Genes Involved in C. elegans Sterol Metabolism.

Cholesterol is required for the normal growth and reproduction of C. elegans. In mammalian cells, cytochrome P450 enzymes chemically convert cholesterol into small molecule ligands for nuclear receptors and other signaling proteins. To investigate whether sterols regulate worm physiology, we tested the effects of mammalian sterol biosynthesis inhibitors on worm growth, reproduction, and lifespan. Among those studied, a class of imidazole based inhibitors: ketoconazole, miconazole, sulconazole, and clotrimazole, each of which inhibits a broad yet unique spectrum of P450 enzymes, significantly affected C. elegans growth, reproduction, and lifespan. At low concentrations (100 micromolar ketoconazole), the inhibitors reduced growth rates and brood size, phenotypes similar to those observed in worms grown on cholesterol-deficient media. At intermediate concentrations (200 micromolar ketoconazole), worms displayed severe growth defects, remaining at L1 or L2 for at least seven days. At high concentrations (300 micromolar ketoconazole), worms died at L1 or L2. In addition, the inhibitors significantly reduced adult lifespan. We are pursuing genetic and genomic strategies to identify signaling pathways modulated by these inhibitors.

Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes

In C. elegans, the cytochrome P450 DAF-9 is required for environmental stimuli to induce dauer recovery. To test whether a similar pathway exists in parasitic nematodes, we used ketoconazole, a broad-spectrum inhibitor for P450s that is known to block steroid hormone synthesis in mammals (20). Ketoconazole completely abolished iL3 recovery induced by serum/GSM and this inhibition was overcome by pharmacological supplementation of Δ7-DA (Fig. 4D), suggesting that a P450 is required for parasitic nematodes' response to host stimuli


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