Abstract
The selectivity of microbial inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT) toward the two isozymes, ACAT1 and ACAT2, was assessed in cell-based assays. Purpactin A (IC50 values of ACAT1 vs. IC50 values of ACAT2; 2.5 microM vs. 1.5 microM), terpendole C (10 microM vs. 10 microM), glisoprenin A (4.3 microM vs. 10 microM), spylidone (25 microM vs. 5.0 microM) and synthetic CL-283,546 (0.1 microM vs. 0.09 microM) inhibited ACAT1 and ACAT2 to similar extents. Beauveriolides I (0.6 microM vs. 20 microM) and III (0.9 microM vs. >20 microM) inhibited ACAT1 rather selectively, while pyripyropenes A (>80 microM vs. 0.07 microM), B (48 microM vs. 2.0 microM), C (32 microM vs. 0.36 microM) and D (38 microM vs. 1.5 microM) showed selective inhibition against ACAT2. In particular, pyripyropene A was found to be the most selective ACAT2 inhibitor with a selective index of more than 1,000.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CHO Cells
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Cholesterol Esters / biosynthesis
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Cricetinae
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Cricetulus
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Depsipeptides / pharmacology
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Diterpenes / pharmacology
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Enzyme Inhibitors / pharmacology*
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Fatty Alcohols / pharmacology
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Heterocyclic Compounds, 3-Ring / pharmacology
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Indoles / pharmacology
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Isoenzymes / antagonists & inhibitors
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / metabolism
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Mice
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Molecular Structure
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Phenanthrenes / pharmacology
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Phenylurea Compounds / pharmacology
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Pyridines / pharmacology
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Sesquiterpenes / pharmacology
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Spiro Compounds / pharmacology
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Sterol O-Acyltransferase / antagonists & inhibitors*
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Sterol O-Acyltransferase 2
Substances
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CL 283,546
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Cholesterol Esters
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Depsipeptides
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Diterpenes
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Enzyme Inhibitors
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Fatty Alcohols
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Heterocyclic Compounds, 3-Ring
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Indoles
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Isoenzymes
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Phenanthrenes
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Phenylurea Compounds
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Pyridines
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Sesquiterpenes
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Spiro Compounds
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spylidone
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terpendole C
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purpactin A
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glisoprenin A
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pyripyropene A
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beauverolides
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Sterol O-Acyltransferase
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sterol O-acyltransferase 1