Cytochrome p‐450: Target for itraconazole

Abstract

Cytochrome P-450: Target for itraconazole. Drug Dev. Res. 8:287-298, 1986.The N-substituted triazole, itraconazole, has high affinity for the cytochrome P-450 (cyt. P-450) isozyme involved in the 14a-demethylation of lanosterol in Candida albicans microsomes. Fifty per cent inhibition was already observed at itraconazole concentations < 5x lo-' M. Higher concentrations (> lo-' M) of this antifungal are needed to interfere with the 14 a-demethylation in mammalian cells. Unlike ketoconazole, itraconazole does not significantly affect in vitro androgen, gluco-and mineralocorticoid steroidogenesis. ltraconazole also does not affect the cyt. P-450-dependent 19-hydroxylation of testosterone, a step in the conversion of androgens to estrogens. The l-hydroxylation of testosterone by pig testes microscomes is only slightly inhibited. It is hypothesized that itraconazole's selective activity on ergosterol biosynthesis is due to its high affinity for the apoprotein of the C. albicans cyt. P-450 involved in the 1401-demethylation of lanosterol.

Overview of medically important antifungal azole derivatives

“…Summaries of the toxicity and adverse reactions of itraconazole recently have been reviewed by De Coster et al (64), Van Cauteren et al (314), and Vanden Bossche et al (326,327). Subchronic toxicity studies in experimental animals demonstrated that the potential target organs for toxicity are the gastrointestinal tract, the mononuclear phagocytizing system, and the adrenals, although the activity observed was less than that seen with ketoconazole (313,314).…”

“…The effects of itraconazole on the pituitary-testicularadrenal axis have been studied extensively (64,326,327). Daily administration of itraconazole at 100 mg for 1 month in human volunteers revealed that basal or luteinizing hormone-releasing hormone-stimulated plasma prolactin, follicle-stimulating hormone, and luteinizing hormone concentrations were not affected.…”

“…Vanden Bossche et al (326,327) determined that itraconazole is a highly selective inhibitor of cytochrome P-450-dependent ergosterol biosynthesis. These authors hypothesized that itraconazole has a high affinity for the apoprotein of fungal cytochrome P-450 involved in the C-14 demethyl- (93)(94)(95).…”

“…There is a growing body of evidence that the primary mode of action of these antifungal drugs is the inhibition of ergosterol biosynthesis in the cytoplasmic membrane of fungi, resulting in the accumulation of lanosterol or other sterol intermediates (25,290,325). Vanden Bossche and co-workers (325)(326)(327) and other investigators (186,270) have demonstrated with a number of antifungal azole derivatives that these compounds affect cytochrome P-450 involved in the 14a-demethylation of lanosterol. Fluconazole and itraconazole are more selective for the fungal cytochrome P-450 isozymes than is ketoconazole; thus, mammalian physiology is less seriously disturbed by the newer triazoles as compared to the imidazole ketoconazole.…”

The Use of Swiss Albino Mice and Egyptian Toads (Bufo regularis) as Reliable Biological Test Animals for Screening Chemicals and Drugs Which Induce Leukaemia in Man. I: The Effect of Nizoral (Ketoconazole) on Leucocytes of Toads and Mice

“…Ketoconazole (Nizoral) inhibits steroid biosynthesis in patients as it does in fungi by inhibition of cytochrome P 450 dependent enzymes (Loose et al, 1983). Thus nizoral impairs the biosynthesis of ergosterol for the cytoplasmic membrane and lead to the accumulation of 14-α methyl sterols (Vanden Bossche et al, 1986). These methyl sterols may disrupt the close packing of acyl chains of phospholipids, impairing the function of certain membrane-bound enzyme systems and inhibiting growth of fungi (Bennett, 1991).…”