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
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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Keywords: oxysterols, cholesterol, biosynthesis, regulation, Hep G2 cells, side chain conformation
Citation:
Mehtiev A.R., Fedchenko V.I., Tkachev Ya.V., Timofeev V.P., Misharin A.Yu. (2010) Regulation of cholesterol biosynthesis and metabolismin Hep G2 cells by δ8(14)-15-ketoergostane derivatives. Biomeditsinskaya Khimiya, 56(5), 576-586.
Mehtiev A.R. et al. Regulation of cholesterol biosynthesis and metabolismin Hep G2 cells by δ8(14)-15-ketoergostane derivatives // Biomeditsinskaya Khimiya. - 2010. - V. 56. -N 5. - P. 576-586.
Mehtiev A.R. et al., "Regulation of cholesterol biosynthesis and metabolismin Hep G2 cells by δ8(14)-15-ketoergostane derivatives." Biomeditsinskaya Khimiya 56.5 (2010): 576-586.
Mehtiev, A. R., Fedchenko, V. I., Tkachev, Ya. V., Timofeev, V. P., Misharin, A. Yu. (2010). Regulation of cholesterol biosynthesis and metabolismin Hep G2 cells by δ8(14)-15-ketoergostane derivatives. Biomeditsinskaya Khimiya, 56(5), 576-586.
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