[Regulation of cholesterol biosynthesis and metabolism in Hep G2 cells by delta8(14)-15-ketoergostane derivatives].
The comparative study of effects of 5alpha-cholest-8(14)-en-15-on-3beta-ol (I), (22E)-5alpha-ergosta-8(14),22-dien-15-on-3beta-ol (II), (22S,23S)-22,23-oxido-5alpha-ergost-8(14)-en- 15-on-3beta-ol (III) and (22R,23R)-22,23-oxido-5alpha-ergost-8(14)-en-15-on-3beta-ol (IV) on HMG-CoA reductase, CYP27A1 and CYP3A4 genes expression in Hep G2 cells was performed. In the contrast to 15-ketocholestane derivative (I), 15-ketoergostane derivatives (II - IV) decreased the HMG- CoA reductase mRNA level; (22R,23R)-22,23-oxido-5alpha-ergost-8(14)-en-15-on-3beta-ol (IV) significantly increased CYP3A4 mRNA level (320% from control). Ketosterol (II) was found to be a more potent inhibitor of cholesterol biosynthesis in Hep G2 cells at a prolong incubation, compared with ketosterol (I). The side chain conformation of compounds (I) - (IV) was evaluated by computational modeling; the correlation between biological activity of these compounds and conformational flexibility of their side chains was found. The results obtained indicated that delta8(14)-15-ketoergostane derivatives may be used as a sterol biosynthesis and metabolism regulators in liver cells.
A R
AR
Mekhtiev
V I
VI
Fedchenko
Ia V
IaV
Tkachev
V P
VP
Timofeev
A Iu
AIu
Misharin
D002784:Cholesterol / Q000096:biosynthesis*; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism*
D002784:Cholesterol; C015190:ergostane; D004875:Ergosterol