The Effect of 15-Ketosterol Analogues with a 5,6-Dimethylhept-3-en-2-yl Chain at C17 on Cholesterol Metabolism in Hep G2 Hepatoma Cells

Abstract

The effect on cholesterol metabolism in Hep G2 hepatoma cells was studied for new analogues of 15-ketosterol [3beta-hydroxy-5alpha-cholest-8(14)-en-15-one] (I): (24S)-3beta-hydroxy-24-methyl-5alpha-cholesta-8(14),22-diene-15-one (II), (24S)-3alpha-hydroxy-24-methyl-5-alpha-cholesta-8(14),22-diene-15-one (III), and (24S)-24-methyl-5alpha-cholesta-8(14),22-diene-3,15-dione (IV). Analogues (I) and (II) were found to be equally effective inhibitors of cholesterol biosynthesis after a 3-h incubation with Hep G2 cells; however, (II) produced a stronger inhibitory effect after a 24-h incubation or after an incubation of cells preliminarily treated with the inhibitor in a medium containing no ketosterol. The ability of ketosterols to inhibit cholesterol biosynthesis decreased in the order (II) > (IV) > (III). Ketosterol (II) inhibited, whereas ketosterol (III) stimulated the biosynthesis of cholesteryl esters. (IV) stimulated the biosynthesis of cholesteryl esters at a concentration of 1-10 microM and exerted no marked effect at a concentration of 30 microM. These results indicate that delta8(14)-15-ketosterols containing a modified side chain are of interest as regulators of cholesterol metabolism in liver cells. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 5; see also http: // www.maik.ru.

Metabolism of a novel side chain modified Δ8(14)-15-ketosterol, a potential cholesterol lowering drug: 28-hydroxylation by CYP27A1

“…Also, the synthetic 15-ketosterol described by Schroepfer and collaborators [7] which has been found to be converted into 27-hydroxylated product by rat liver mitochondria [18] was examined in our experiments. Indeed, our experiments with recombinant human CYP27A1 enzyme showed CYP27A1-mediated metabolism of the novel side-chain modified Δ8(14)-15ketosterol synthesized by Misharin and coworkers [10,11] as well as of the Δ8(14)-15ketosterol originally described by Schroepfer et al [7]. However, the rate of metabolism of the side-chain modified 15-ketosterol, 3β-hydroxy-24S-methyl-5α-cholesta-8 (14),22-dien-15one, was much lower.…”

“…One of these, 3β-hydroxy-24S-methyl-5α-cholesta-8 (14),22-dien-15one, was found to have an inhibiting potency of cholesterol biosynthesis that exceeded that of the 15-ketosterol described by Schroepfer and collaborators [7,10,11]. Furthermore, the new side-chain modified 15-ketosterol produced a stronger inhibitory effect after longer incubation times [10][11]. The structures of the two 15-ketosterols studied in this paper are shown in Fig.…”

“…3β-Hydroxy-5α-cholest-8(14)-en-15-one was obtained from Avanti Polar Lipids. Inc. 3β-Hydroxy-24S-methyl-5α-cholesta-8 (14),22-dien-15-one was synthesized as described by Misharin [10,11]. 27-Hydroxycholesterol, prepared from kryptogenin, was kindly provided by Dr. L. Tökes, Syntex, Palo Alto, CA, USA.…”

“…A group of side-chain modified analogues of the 15-ketosterol described by Schroepfer et al [7], potently inhibiting cholesterol synthesis and possessing strong hypocholesterolemic activity in vivo, has been synthesized by Misharin and collaborators [10,11]. One of these, 3β-hydroxy-24S-methyl-5α-cholesta-8 (14),22-dien-15one, was found to have an inhibiting potency of cholesterol biosynthesis that exceeded that of the 15-ketosterol described by Schroepfer and collaborators [7,10,11]. Furthermore, the new side-chain modified 15-ketosterol produced a stronger inhibitory effect after longer incubation times [10][11].…”

New Δ8(14)-15-Ketosterols with an Oxygenated Side Chain

“…2 Previously, on the basis of works [2][3][4][5], we had presumed that the ∆ 8(14)-15-ketosterols with a modified chain at C17 that is resistant to the oxidative cleavage at C24 in hepatocytes could be of interest as the bioregulators of cholesterol biosynthesis and synthesized (22 E ,24 S )-3 βhydroxy-24-methyl-5 α -cholesta-8 (14),22-diene-15-one (along with its corresponding 3 α -epimer and 3,15dione) from ergosterol [6]. This compound proved to be an effective inhibitor of biosynthesis of cholesterol and cholesteryl esters in the cells of human hepatoma Hep G2 [7].…”