ABSTRACT

This chapter discusses the effects of a number of ergosterol biosynthesis inhibitors on P450-dependent reactions in mammalian cells. It focuses on those interactions that could contribute to the development of new possibilities in medical treatment. A key step in the biosynthesis of the 24-alkylated sterol, ergosterol, is the cytochrome P-450-(P450) dependent 14α-demethylation of lanosterol or 24-methylenedihydrolanosterol in most pathogenic fungi. In the P450 cycle, a number of steps are vulnerable to inhibition. Examples are the binding of the substrate, the interaction between the P450 reductase and P450, the binding of molecular oxygen, and the transfer of an oxygen atom to the substrate. P450 systems were of help in the selection of the triazole antifungal itraconazole, which shares it broad spectrum of oral activity with ketoconazole but is much more active against, e.g., Aspergillus fumigatus and Sporothrix schenckii, and is highly active in meningeal cryptococcosis.