Regulation of cholesterol biosynthesis and metabolismin Hep G2 cells by δ8(14)-15-ketoergostane derivatives

   


1. V.N. Orekhovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences
2. V.A. Engelghardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
Type: Experimental/clinical study
DOI: 10.18097/pbmc20105605576      UDK: 547.92.057      PubMed Id: 21254628
Year: 2010 vol: 56  issue:5  pages: 576-586
Abstract: The comparative study of effects of 5α-cholest-8(14)-en-15-on-3β-ol (I), (22E)-5α-ergosta-8(14),22-dien-15-on-3β-ol (II), (22S,23S)-22,23-oxido-5α-ergost-8(14)-en-15-on-3β-ol (III) and (22R,23R)-22,23-oxido-5α-ergost-8(14)-en-15-on-3β-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-5α-ergost-8(14)-en-15-on-3β-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 Δ8(14)-15-ketoergostane derivatives may be used as a sterol biosynthesis and metabolism regulators in liver cells.
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Reference: Mehtiev А.R., Fedchenko V.I., Tkachev Ya.V., Timofeev V.Р., Misharin А.Yu., Regulation of cholesterol biosynthesis and metabolismin Hep G2 cells by δ8(14)-15-ketoergostane derivatives, Biomeditsinskaya khimiya, 2010, vol: 56(5), 576-586.
This paper is also available as the English translation:10.1134/S1990750810030066
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