Effect of 3-substituted Delta 8(14)-15-ketosterols on cholesterol metabolism in hepatoma Hep G2 cells

The effects of 3-substituted Delta 8(14)-15-ketosterols-3 beta-(2-hydroxyet hoxy)-, 3 beta-(2-propenyloxy)-, 3 beta-[2(R,S),2,3-oxidopropyloxy]-, 3 bet a-[2(R,S),2,3 -dihydroxypropyloxy]-, 3 beta-(2-oxoethoxy)-, 3 beta-[2(R,S), 2-acetoxy-3-acetamidopropyloxy]-, and 3 beta-[2(R,S),2-hydroxy-3-acetamidop ropyloxy]-5 alpha-cholest-8(14)-en-15-ones-on cholesterol metabolism were s tudied in human hepatoma Hep G2 cells. 3 beta-(2-Propenyloxy)-, 3 beta-(2-9 xoethoxy)-, and 3 beta-[2(R,S),2,3-oxidopropyloxy]-5 alpha-cholest-8(14)-en -15-ones inhibited cholesterol biosynthesis without any effect on triglycer ide biosynthesis, while 3 beta-[2(R,S),2-acetoxy-3-acetamidopropyloxy]- and 3 beta-[2(R,S),2-hydroxy3-acetamidopropyloxy]-5 alpha-cholest-8( 14)-en-15 -ones inhibited both cholesterol biosynthesis and triglyceride biosynthesis at concentrations exceeding 10 mu M 3 beta-[2(R,S),2,3-Dihydroxypropyloxy] -5 alpha-cholest-8(14)-en-15-one, effectively inhibiting cholesterol biosyn thesis, was found also to be toxic in Hep G2 cells at micromolar concentrat ions. 3 beta-[2(R,S),2,3-Oxidopropyloxy]-5 alpha-cholest-8(14)-en-15-one ef fectively inhibited cholesterol acylation. All the tested compounds decreas ed the HMG-CoA reductase mRNA level at concentrations exceeding 10 mu M; ho wever, they did not affect the LDL receptor mRNA level. Among the compounds tested, only 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one decreased the uptake and internalization of LDL-associated cholesteryl eaters, being as e ffective as 25-hydroxycholesterol.