Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties
| Autor: | Tsuyoshi Noguchi, Hiroshi Shimizu, Masami Muraoka, Katsuhisa Ioriya, Katsuya Fujita, Naohito Ohashi |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Sterol O-acyltransferase Mice chemistry.chemical_compound Cricetinae Microsomes Internal medicine medicine Animals Urea Enzyme Inhibitors Naphthyridines Rats Wistar IC50 Inhibitory effect Cells Cultured Pharmacology Chemistry Cholesterol Anticholesteremic Agents Reverse cholesterol transport Esters General Medicine Small intestine Rats Intestines Mice Inbred C57BL medicine.anatomical_structure Endocrinology Macrophages Peritoneal Microsomes Liver Microsome ACAT activity lipids (amino acids peptides and proteins) Rabbits Sterol O-Acyltransferase |
| Zdroj: | Pharmacology. 65:18-25 |
| ISSN: | 1423-0313 0031-7012 |
| DOI: | 10.1159/000056181 |
| Popis: | We investigated the effects of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activities in the liver and intestine, and in macrophages. We measured its effects on the serum cholesterol levels and hepatic cholesterol content in mice, rabbits and hamsters. SMP-500 inhibited ACAT activities in rabbit liver and small intestine microsomes with IC50 values of 72 and 84 nmol/l, respectively, and acted as a competitive inhibitor of rabbit liver ACAT. SMP-500 potently inhibited cholesterol esterification in rat peritoneal macrophages (IC50 = 15 nmol/l). In high-fat and high-cholesterol diet-fed mice and in high-cholesterol diet-fed rabbits, SMP-500 reduced the serum cholesterol levels and the hepatic cholesterol content. SMP-500 also reduced the serum and hepatic cholesterol in normal chow-fed hamsters in a dose-dependent manner. In all the animal models, SMP-500 reduced the hepatic free cholesterol content as well as the total and esterified cholesterol. Administered orally, SMP-500 had a direct inhibitory effect on hepatic ACAT activity. These results indicate that SMP-500 is a potent and competitive ACAT inhibitor and may have a therapeutic potential for treating hypercholesterolemia and atherosclerosis. |
| Databáze: | OpenAIRE |
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