Effect of sterol biosynthesis inhibitor, SSF-109, on cholesterol synthesis in isolated rat hepatocytes.
The inhibitory effect of SSF-109 on cholesterol synthesis in isolated hepatocytes was studied using a radio-high-performance liquid chromatography system, and the results were compared with those of other inhibitors, triparanol and AMO-1618. SSF-109 caused accumulation of two trimethylsterols: lanosterol and 24-dihydrolanosterol. The distribution profile of [2-14C]mevalonate-originated radioactivity in cholesterol, lanosterol, dihydrolanosterol, 2,3-oxidosqualene, and squalene indicates that SSF-109 inhibits the 14 alpha-methyl demethylase activity. Triparanol accumulated the radioactivity of [2-14C]mevalonate in desmosterol and 2,3-oxidosqualene suggesting that triparanol inhibits sterol delta 24-reductase and 2,3-oxidosqualene cyclase. AMO-1618 caused enrichment of the radioisotope from [2-14C]mevalonate in 2,3-oxidosqualene but reduced it in squalene, suggesting that AMO-1618 acts on 2,3-oxidosqualene cyclase and some enzyme that catalizes a metabolic pathway between mevalonate and squalene.
Seo
S
S
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Tonda
K
K
Uomori
A
A
Takeda
K
K
Hirata
M
M
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D002851:Chromatography, High Pressure Liquid; D007810:Lanosterol / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013185:Squalene / Q000378:metabolism; D013261:Sterols / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*
D013261:Sterols; D014230:Triazoles; C081017:4-chlorophenyl-2-(1H-1,2,4-triazol-yl)cycloheptanol; D007810:Lanosterol; D013185:Squalene; D002784:Cholesterol; D008798:Mevalonic Acid