Elastic deformation and failure of lipid bilayer membranes containing cholesterol.

(1983). Sterol, Structure and Membrane Function. Critical Reviews in Biochemistry: Vol. 14, No. 1, pp. 47-92.

Sterol structure and membrane function.

Ordering effects of cholesterol and its analogues

Cytochrome P450s (P450s) are subject to inhibition/inactivation by various chemically diverse agents, which may interact directly or indirectly with either the P450 prosthetic heme or the protein moiety or with both moieties. This inhibition is clinically relevant, as it can block physiological pathways as well as result in therapeutically significant beneficial or adverse effects and clinically relevant drug–drug interactions. Herein, we discuss the various chemical agents and their chemical mechanisms that lead to such reversible, quasi-irreversible, or irreversible inhibition of these enzymes. We note that such inhibition targeted at P450-dependent physiological and/or pathological processes has been ingeniously and effectively harnessed not only in the design and development of clinically relevant therapeutic agents but also of fungicides, insecticides, and herbicides.

Inhibition of Cytochrome P450 Enzymes

Ketoconazole, an orally active antimycotic drug, is a potent inhibitor of ergosterol biosynthesis in Candida albicans when added to culture media which support yeast or mycelial growth or to cultures containing outgrown mycelium. This inhibition coincides with accumulation of sterols with a methyl group at C-14 and can thus be attributed to an interference with one of the reactions involved in the removal of the 14 alpha-methyl group of lanosterol. When administered to rats infected with C. albicans, ketocanazole also inhibits fungal synthesis of ergosterol. A six-times-higher dose is required to effect cholesterol synthesis by rat liver.

In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis.

The effects of cholesterol, 4,4-dimethylcholesterol, and lanosterol (4,4',14α-trimethyl-δ 8,24 -cholestadiene-3β-ol) on some properties of lecithin vesicles have been compared. Unlike cholesterol, lanosterol retards the exit of trapped glucose from phospholipid vesicles only slightly. The 13 C nuclear magnetic resonance spectrum of cholesterol/lecithin vesicles shows no resonances attributable to the sterol. By contrast, several resonances attributable to quaternary carbon atoms or methyl groups are seen in the 13 C nuclear magnetic resonance spectrum of lanosterol/lecithin vesicles, indicating that lanosterol is much less immobilized than cholesterol. Because the membrane behavior of 4,4-dimethylcholesterol is closely similar to that of cholesterol, it is concluded that the axial 14-α-methyl group is responsible for the lessened membrane immobilization of lanosterol. The results emphasize the importance of a planar sterol α-face for interaction with phospholipid acyl chains.

P. L. Yeagle

Papers

Differential effects of cholesterol and lanosterol on artificial membranes (glucose permeability/ 13 C nuclear magnetic resonance spectroscopy)