Oxidative metabolism of cholesterol precursors: sensitivity to ketoconazole, an inhibitor of cytochrome P-450.
The effects of ketoconazole, an inhibitor of cytochrome P-450, on the metabolism of the cholesterol precursors lanosterol, dihydrolanosterol, lanost-8-en-3 beta,32-diol, and 3 beta-hydroxylanost-8-en-32-al were investigated in subcellular fractions of rat liver and in rat hepatocytes in culture. At low (1-2 microM) concentrations of the drug, the oxidative demethylation of lanosterol was inhibited by about 70% in the subcellular fractions but there was no effect on the metabolism of the 3 beta, 32-diol or the 32-aldehyde. Higher drug concentrations (10-20 microM) were required to inhibit the oxidative metabolism of these cholesterol precursors. Similar results were obtained during longer-term incubations using hepatocytes in culture medium, but higher concentrations of ketoconazole were required to effect the same degree of inhibition of each precursor. In the subcellular fractions, dihydrolanosterol, the 3 beta,32-diol and the 32-aldehyde were each metabolized to more polar sterols, in addition to cholesterol. Ketoconazole also inhibited the formation of these polar substances.
Iglesias
J
J
Metabolic Research Laboratory, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, UK.
Gibbons
G F
GF
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D007654:Ketoconazole / Q000494:pharmacology*; D007810:Lanosterol / Q000031:analogs & derivatives / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013261:Sterols / Q000378:metabolism; D013347:Subcellular Fractions
D013261:Sterols; D007810:Lanosterol; C050483:32-hydroxy-24,25-dihydrolanosterol; C032444:lanosten-3-ol-32-al; D002784:Cholesterol; D007654:Ketoconazole