Effect of CS-514, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, on cholesterol gallstone formation in hamsters.
Male golden hamsters fed a glucose diet as a model for cholesterol gallstone formation were used to investigate the effect of CS-514 on the lithogenicity of bile. Treatment with 0.05% (w/w) CS-514 in the diet for 1-4 weeks caused a decrease in plasma cholesterol and triacylglycerol levels. A marked increase in hepatic hydroxymethylglutaryl-CoA reductase activity in vitro and also an increased de novo cholesterol synthesis in the liver were induced by treatment with CS-514 for 1-4 weeks. The concentration of free cholesterol in liver microsomes and the cholesterol 7 alpha-hydroxylase activity were both decreased by treatment with CS-514 for 1 week, but were not affected by treatment for 4 weeks. The cholesterol output into bile and the lithogenic index of bile were double those of the control (glucose diet only) following treatment with CS-514 for 4 weeks, and the subsequent incidence of cholesterol gallstone formation was elevated. The content of free cholesterol and cholesterol ester in the liver was not affected by treatment with CS-514 for 4 weeks. These results suggest that long-term treatment with CS-514 causes a compensatory increase in the synthesis of hydroxymethylglutaryl-CoA reductase which leads to augmented hepatic de novo cholesterol synthesis and subsequent increased cholesterol output followed by an increase in the lithogenicity of bile. CS-514 apparently does not prevent cholesterol gallstone formation in those examples where the mechanism is thought to be due to augmented hepatic de novo cholesterol synthesis (type IV hyperlipidemia).
Koide
K
K
First Department of Internal Medicine, Hiroshima University School of Medicine, Japan.
Hayashi
K
K
Horiuchi
I
I
Kajiyama
G
G
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002769:Cholelithiasis / Q000139:chemically induced*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D006224:Cricetinae; D004040:Dietary Carbohydrates; D005947:Glucose; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D050356:Lipid Metabolism; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology*; D017035:Pravastatin; D012016:Reference Values; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D004040:Dietary Carbohydrates; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009281:Naphthalenes; D014280:Triglycerides; D002784:Cholesterol; D005947:Glucose; D017035:Pravastatin