Lanosterol, inhibition demethylation

A) It is highly effective in treatment of aspergillosis It does not penetrate the blood-brain barrier Its oral bioavailability is less than that of ketoconazole It inhibits demethylation of lanosterol It is a potent inhibitor of hepatic drug-metabolizing enzymes... 

Mode of action Ketoconazole interacts with C-14 a-demethylase (a cytochrome P-450 enzyme) to block demethylation of lanosterol to ergosterol, the principal sterol of fungal membranes Figure 34.4). This inhibition disrupts membrane function and increases permeability. Ketoconazole acts in an additive manner with flucytosine against Candida, but antagonizes amphotericin B s antifungal activity. 

In our laboratory, the major sterol biosynthesised in untreated extracts was the triene (VIII) (1J), rather than ergosterol Itself which is, of course, the end product of the pathway in intact cells. It should be noted that VIII arises directly from 14-demethylation of lanosterol. In the presence of 0.1 yM prochloraz (or even 0.01 pM prochloraz in some experiments) the concentration of VIII was significantly reduced, while the level of lanosterol Increased (4) indicating clearly that prochloraz inhibited 14-demethylation. At higher fungicide concentrations both the triene and ergosterol were totally absent and only lanosterol was present. 

Since ergosterol is used in the formation of the leishmanial cell membrane, inhibition of ergosterol biosynthesis has been considered as a useful target for chemotherapeutic attack. Allylamines (eg. terbinafine) and imidazole antifungals (eg. ketoconazole) have been found to interfere with different steps in the biosynthetic pathway of C28 sterols in leishmania and fungi. Allylamines inhibit the microsomal squalene 2,3-epoxidase and, therefore, inhibit the synthesis of squalene epoxide, the precursor of lanosterol. Imidazoles, on other hand, inhibit cytochrome P-450 dependent C-14 demethylation of lanosterol leading to decreased or no synthesis of ergosterol [30]. 

Azoles are fungicidal and interfere with the synthesis of ergosterol by inhibiting the P450-dependent 14 alpha-demethylation of its precursor molecule, lanosterol. 

As indicated, the oxidative demethylation of lanosterol in rat liver preparations is inhibited by CO. However, if 32-hydroxylanosterol is used as substrate, CO no longer inhibits. This indicates that in animals cytochrome P-450 catalyzes only the first oxidation and that other cytochromes are used in the subsequent steps. Apparently, the yeast and liver systems are different [5]. 

Inhibition of Demethylation of Lanosterol at C-14 and Other Effects on Lipid Metabolism ... 

This response has been attributed to a decreased rate of HMG-CoA reductase synthesis (28-30) and in some instances to an increase in enzyme degradation (28-30). Other oxysterols are known to depress the rate of cholesterol synthesis from lanosterol in rat liver homogenates and may inhibit the 14-demethylation of lanosterol (31-33). 

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