Subject(s)
Cellulose/metabolism , Diet , Sterols/metabolism , Absorption , Animals , Bile Acids and Salts/biosynthesis , Bile Acids and Salts/metabolism , Body Weight , Cholesterol/biosynthesis , Cholesterol/blood , Cholic Acids , Chromatography, Gas , Chromatography, Thin Layer , Defecation , Energy Metabolism , Feces/analysis , Intestinal Absorption , Lignin/metabolism , Liver/metabolism , Male , Rats , Steroid Hydroxylases/analysis , Sterols/biosynthesis , VegetablesABSTRACT
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.
Subject(s)
Anticholesteremic Agents/pharmacology , Ethers, Cyclic/isolation & purification , Imidazoles/pharmacology , Liver/analysis , Squalene/isolation & purification , Acetates/metabolism , Animals , Carbon Isotopes , Cholesterol/blood , Chromatography, Thin Layer , In Vitro Techniques , Liver/drug effects , Liver/metabolism , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mevalonic Acid/metabolism , RatsABSTRACT
1. Adjuvant-induced arthritis in rats is accompanied by a loss of activity of the drug-metabolizing enzyme system and a decrease in hepatic cytochrome P-450. 2. Arthritic rats have normal serum and liver cholesterol concentrations. 3. The rate of biogenesis of cholesterol in vivo and in vitro from either [(14)C]acetate or [(14)C]mevalonate in arthritic rats was the same as or greater than that found in control rats. 4. Treatment of rats with carbon disulphide (1ml/kg) resulted in a loss of drug-metabolizing-enzyme activity and increased cholesterol biogenesis. 5. The activity of cholesterol 7alpha-hydroxylase in adjuvant-induced arthritic rats did not differ significantly from that in control rats. 6. Rats fed with cholestyramine had an elevated hepatic cholesterol 7alpha-hydroxylase activity, but neither the concentration of cytochrome P-450 nor the activity of the drug-hydroxylating enzyme, aminopyrine demethylase, was affected. 7. The relationships between drug hydroxylation and cholesterol metabolism are discussed.
