Pharmacological profile of SMP-797, a novel acyl-coenzyme a: cholesterol acyltransferase inhibitor with inducible effect on the expression of low-density lipoprotein receptor.
We investigated the pharmacological profile of SMP-797, a novel hypocholesterolemic agent. SMP-797 showed inhibitory effects on acyl-coenzyme A: cholesterol acyltransferase (ACAT) activities in various microsomes and in human cell lines, and hypocholesterolemic effects in rabbits fed a cholesterol-rich diet and hamsters fed a normal diet. In hamsters, the reduction of total cholesterol level by SMP-797 was mainly due to the decrease of low-density lipoprotein (LDL) cholesterol level rather than that of very low-density lipoprotein (VLDL) cholesterol level. Interestingly, SMP-797 increased the hepatic low-density lipoprotein receptor expression in vivo when it decreased the low-density lipoprotein cholesterol level. SMP-797 also increased low-density lipoprotein receptor expression in HepG2 cells like atorvastatin, an HMG-CoA reductase inhibitor, although other acyl-coenzyme A: cholesterol acyltransferase inhibitor had no effect. In addition, SMP-797 had no effect on cholesterol synthesis in HepG2 cells. These results suggested that the increase of low-density lipoprotein receptor expression by SMP-797 was independent of its acyl-coenzyme A: cholesterol acyltransferase inhibitory action and did not result from the inhibition of hepatic cholesterol synthesis. In conclusion, these results suggest that SMP-797 is a novel hypocholesterolemic agent showing a cholesterol-lowering effect in which the increase of hepatic low-density lipoprotein receptor expression as well as the inhibition of acyl-coenzyme A: cholesterol acyltransferase is involved.
Ioriya
Katsuhisa
K
Research Division, Sumitomo Pharmaceuticals Co., Ltd., Osaka, Japan.
Kino
Kouichi
K
Horisawa
Seiya
S
Nishimura
Takeshi
T
Muraoka
Masami
M
Noguchi
Tsuyoshi
T
Ohashi
Naohito
N
D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011973:Receptors, LDL / Q000187:drug effects* / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D000214:Acyl Coenzyme A; D000924:Anticholesteremic Agents; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D011973:Receptors, LDL; C508738:SMP-797; D002784:Cholesterol; D002785:Sterol O-Acyltransferase