Glibenclamide acts as an inhibitor of acyl-CoA:cholesterol acyltransferase enzyme.
Sulfonylureas are used in the treatment of non-insulin-dependent diabetes mellitus. Little is known, however, about their effects on cholesterol metabolism. We tested in the present study the effects of glibenclamide (GB) on cholesterol esterification (CE) in macrophage-derived cells. GB inhibited intracellular accumulation of CE induced by acetylated LDL or oxidized LDL in J774 cells, but no such effect on total cholesterol, suggesting that the target of GB was acyl-CoA:cholesterol acyltransferase (ACAT). In the cell-free reconstitution ACAT assay, GB inhibited the ACAT activity with an IC(50) value of 20 microM. Furthermore, GB effectively inhibited the ACAT activity of PMA-stimulated THP-1 cells to the undifferentiated level of THP-1. In the whole-cell ACAT assay using CHO cells overexpressed with ACAT-1 or ACAT-2, GB inhibited the activity of both isozymes with similar potency. Our in vitro data suggest that sulfonylurea could be a potential seed for a new generation of ACAT inhibitors.
Ohgami
N
N
Department of Biofunctional Chemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Ohe-Honmachi, Kumamoto, 862-0973, Japan.
Kuniyasu
A
A
Furukawa
K
K
Miyazaki
A
A
Hakamata
H
H
Horiuchi
S
S
Nakayama
H
H
D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002474:Cell-Free System; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003510:Cyclohexanes / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000813:Anilides; D000814:Aniline Compounds; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007527:Isoenzymes; D008077:Lipoproteins, LDL; C111531:NTE 122; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein; C069304:PD 128042; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase; D002785:Sterol O-Acyltransferase; D013755:Tetradecanoylphorbol Acetate; D005905:Glyburide