The isolation of 2,3-oxidosqualene from the liver of rats treated with 1-dodecylimidazole, a novel hypocholesterolaemic agent.
1. Non-saponifiable lipid from the livers of rats treated with 1-dodecylimidazole contained an unidentified compound that was not present in the livers from untreated animals. 2. Treated rats had lower serum cholesterol concentrations than control rats. 3. 1-Dodecylimidazole, when added to rat liver slices, inhibited the incorporation of [1-(14)C]acetate and [2-(14)C]mevalonate into digitonin-precipitable sterols and resulted in the accumulation of a labelled compound, which was chromatographically identical with the unknown compound described in 1 above. 4. Rats treated with 1-dodecylimidazole incorporated less [(14)C]mevalonate into liver digitonin-precipitable sterols than untreated animals and accumulated the unknown compound as a labelled intermediate. 5. The unknown intermediate had the same chromatographic properties, n.m.r. and mass spectra as authentic 2,3-oxidosqualene. 6. The identity of the intermediate as 2,3-oxidosqualene was further established by showing that it was incorporated into sterols by rat liver homogenates under anaerobic conditions. In addition, incubation of [(14)C]squalene with rat liver homogenates resulted in trapping of the radioactivity by the added intermediate. 7. It is suggested that the hypocholesterolaemic activity of 1-dodecylimidazole results in part from the inhibition of cholesterol biosynthesis at the level of 2,3-oxidosqualene sterol cyclase.
D000085:Acetates / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002247:Carbon Isotopes; D002784:Cholesterol / Q000097:blood; D002855:Chromatography, Thin Layer; D004988:Ethers, Cyclic / Q000302:isolation & purification*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000032:analysis* / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008798:Mevalonic Acid / Q000378:metabolism; D051381:Rats; D013185:Squalene / Q000302:isolation & purification* / Q000031:analogs & derivatives
C002821:2,3-oxidosqualene; D000085:Acetates; D000924:Anticholesteremic Agents; D002247:Carbon Isotopes; D004988:Ethers, Cyclic; D007093:Imidazoles; D013185:Squalene; D002784:Cholesterol; C002822:1-dodecylimidazole; D008798:Mevalonic Acid