Effect of a new synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on cholesterol synthesis and low density lipoprotein uptake by primary cultures of rat hepatocytes.
CS-514 ((+)-sodium (3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2- methyl-8-[(S)-2-methyl-butyryl]-1,2,6,7,8-hexahydro-1-naphthyl] heptanoate) which was recently synthesized as an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase lowers serum cholesterol levels. This compound inhibited cholesterol synthesis dose-dependently from acetate in primary cultures of rat hepatocytes. At high concentration (0.5 and 5.0 mumol/l), but not at lower concentration, it inhibited bile formation from acetate. Low density lipoprotein (LDL)-[3H]-cholesteryl linoleate incorporation into hepatocytes was increased when the cells were preincubated with 0.5 or 5.0 mumol/l CS-514 for 12 h. Bile formation from LDL-[3H]-cholesterol linoleate was not affected by addition of CS-514. These results suggest that inhibition of de novo cholesterol synthesis by CS-514 enhanced LDL receptor function in primary cultures of rat hepatocytes and lowered LDL-cholesterol level.
D000085:Acetates / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D002784:Cholesterol / Q000096:biosynthesis*; D002788:Cholesterol Esters / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D017035:Pravastatin; D051381:Rats; D011919:Rats, Inbred Strains
D000085:Acetates; D001647:Bile Acids and Salts; D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D009281:Naphthalenes; C021976:cholesteryl linoleate; D002784:Cholesterol; D017035:Pravastatin