Effect of E5324, a Novel Inhibitor of Acyl-CoA:Cholesterol Acyltransferase, on Cholesteryl Ester Synthesis and Accumulation in Macrophages
作者： Motoji Kogushi , Hiroshi Tanaka , Hiroko Kobayashi , Toshie Yamada , Issei Ohtsuka
DOI: 10.1254/JJP.68.191
关键词: Enzyme 、 Enzyme inhibitor 、 Microsome 、 Biochemistry 、 Cholesteryl ester 、 Metabolism 、 Chemistry 、 Sterol O-acyltransferase 、 Cholesterol 、 Phorbol 、 Pharmacology
摘要: The in vitro potencies of a novel inhibitor acyl-CoA:cholesterol acyltransferase (ACAT), E5324 (n-butyl-N''-[2-[3-(5-ethyl-4-phenyl-1H-imidazol-1-yl)propoxy]-6-methylphenyl]urea), were studied. was found to be potent ACAT microsomes from various tissues and cultured cell homogenate, with IC50 values the range 0.044 0.19 μM. kinetic study on showed that inhibition rat intestine competitive respect oleoyl CoA. inhibited [3H]oleate incorporation into cholesteryl phorbol ester-treated THP-1 lines (IC50=0.44 tμM). rate phospholipids triglycerides not affected by E5324. In an experiment [3H]cholesterol as substrate for ACAT, also [3H]cholesteryl ester synthesis (IC50=0.41 μM). Furthermore, prevented accumulation both esterified total cholesterol acetyl low density lipoprotein-loaded cells. These results indicate is selective prevents macrophages.
elsevier.com
sci-hub.se 参考文章(33)
E. J. Bartucci, R. W. Wissler, T. Schaffner, S. Glagov, K. Taylor, J. H. Beeson, K. Fischer-Dzoga, Arterial foam cells with distinctive immunomorphologic and histochemical features of macrophages. American Journal of Pathology. ,vol. 100, pp. 57- 80 ,(1980)
C.C. Chang, H.Y. Huh, K.M. Cadigan, T.Y. Chang, Molecular cloning and functional expression of human acyl-coenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells. Journal of Biological Chemistry. ,vol. 268, pp. 20747- 20755 ,(1993) , 10.1016/S0021-9258(19)36846-2
I Tabas, W J Rosoff, G C Boykow, Acyl coenzyme A:cholesterol acyl transferase in macrophages utilizes a cellular pool of cholesterol oxidase-accessible cholesterol as substrate. Journal of Biological Chemistry. ,vol. 263, pp. 1266- 1272 ,(1988) , 10.1016/S0021-9258(19)57295-7
M Shinohara, A Miyazaki, M Shichiri, Y Morino, S Horiuchi, Exposure of rat peritoneal macrophages to acetylated low density lipoprotein results in release of plasma membrane cholesterol. An efficient substrate for esterification by acyl-CoA:cholesterol acyltransferase. Journal of Biological Chemistry. ,vol. 267, pp. 1603- 1608 ,(1992) , 10.1016/S0021-9258(18)45988-1
K E Suckling, E F Stange, Role of acyl-CoA: cholesterol acyltransferase in cellular cholesterol metabolism. Journal of Lipid Research. ,vol. 26, pp. 647- 671 ,(1985) , 10.1016/S0022-2275(20)34322-4
R W Mahley, T L Innerarity, M S Brown, Y K Ho, J L Goldstein, Cholesteryl ester synthesis in macrophages: stimulation by beta-very low density lipoproteins from cholesterol-fed animals of several species. Journal of Lipid Research. ,vol. 21, pp. 970- 980 ,(1980) , 10.1016/S0022-2275(20)34757-X
BR Krause, M Anderson, CL Bisgaier, T Bocan, R Bousley, P DeHart, A Essenburg, K Hamelehle, R Homan, K Kieft, In vivo evidence that the lipid-regulating activity of the ACAT inhibitor CI-976 in rats is due to inhibition of both intestinal and liver ACAT. Journal of Lipid Research. ,vol. 34, pp. 279- 294 ,(1993) , 10.1016/S0022-2275(20)40755-2
M.S. Brown, Y.K. Ho, J.L. Goldstein, The cholesteryl ester cycle in macrophage foam cells. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters. Journal of Biological Chemistry. ,vol. 255, pp. 9344- 9352 ,(1980) , 10.1016/S0021-9258(19)70568-7
Nobuhiro Morisaki, Nobuo Matsuoka, Kohji Shiral, Yasushi Sato, Akira Kumagai, Studies on acyl-CoA synthetase in rat arterial wall Atherosclerosis. ,vol. 37, pp. 439- 447 ,(1980) , 10.1016/0021-9150(80)90149-5
Teiji Kimura, Yasutaka Takase, Kenji Hayashi, Hiroshi Tanaka, Issei Ohtsuka, Takao Saeki, Motoji Kogushi, Toshie Yamada, Tohru Fujimori, Structure-activity relationship of N-[2-(dimethylamino)-6-[3-(5-methyl-4-phenyl-1H-imidazol-1-yl)propoxy] phenyl]-N'-pentylurea and analogues. Novel potent inhibitors of acyl-CoA:cholesterol O-acyltransferase with antiatherosclerotic activity. Journal of Medicinal Chemistry. ,vol. 36, pp. 1630- 1640 ,(1993) , 10.1021/JM00063A013