Effect of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232) on cholesterol metabolism in rats.
The effects of 4-(4'-chlorobenzyloxy)benzyl nicotinate (KCD-232), a new hypolipidemic agent, on serum cholesterol level and cholesterol biosynthesis were studied in normolipidemic rats. KCD-232 dose-dependently reduced the serum cholesterol level. The in vivo incorporation of [14C]-acetate and 3H from [3H]water into liver digitonin-precipitable sterols was inhibited by oral administration of KCD-232, while that of [14C]mevalonic acid into the sterols was not inhibited. Hepatic 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase activity was suppressed significantly by the oral administration of the drug. A KCD-232 metabolite, 4-(4'-chlorobenzyloxy)benzoic acid (MII), strongly inhibited [14C]acetate incorporation and weakly inhibited [14C]mevalonic acid incorporation into the sterols in liver slices. MII also significantly inhibited the sterol synthetic rate measured with [3H]water and the HMG-CoA reductase activity in dispersed hepatocytes. MII and its CoA thioester (MII-CoA) inhibited the incorporation of [14C]acetate, [14C]acetyl-CoA and [14C]HMG-CoA into nonsaponifiable lipids in a cell-free enzyme system from rat liver. MII-CoA further showed a weak inhibition of [14C]-mevalonic acid incorporation into nonsaponifiable lipids in the system, while MII showed no effect on mevalonic acid incorporation. These results indicate that KCD-232 possesses a major inhibitory site for sterol synthesis on HMG-CoA reductase due to both MII and MII-CoA, and a possible second site of action beyond mevalonic acid due to MII-CoA. The latter inhibitory site, however, is considered to play a minor role in the inhibition of sterol synthesis in vivo.
D000085:Acetates / Q000378:metabolism; D019342:Acetic Acid; D000818:Animals; D002250:Carbon Radioisotopes; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D009539:Nicotinic Acids / Q000494:pharmacology*; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D013261:Sterols / Q000096:biosynthesis; D014316:Tritium
D000085:Acetates; D002250:Carbon Radioisotopes; D000960:Hypolipidemic Agents; D009539:Nicotinic Acids; D013261:Sterols; D014316:Tritium; C042413:4-(4'-chlorobenzyloxy)benzyl nicotinate; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D019342:Acetic Acid; D008798:Mevalonic Acid