Transformation of 3β-(2-Hydroxyethoxy)-5α-cholest-8(14)-en-15-one to a Polar Metabolite in Hepatoma Hep G2 Cells

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Incubation of 3β-(2-hydroxy-2[3H]-ethoxy)-5α-cholest-8(14)-en-15-one with Hep G2 cells led to the accumulation of a radioactive polar product in the culture medium, which was identified as 3β-(2-hydroxyethoxy)-15-keto-5α-cholest-8(14)-ene-24-oic acid. Its structure was confirmed by a chemical counter synthesis. The labeled ketosterol was rapidly (t1/2 = 6 min) and reversibly bound by Hep G2 cells. The intracellular concentration of 15-ketosterol decreased during incubation mainly due to the formation of a polar metabolite, secreted to the medium. The level of cholesterol biosynthesis was 22 ± 5% of the control value in Hep G2 cells at a 15-ketocholesterol concentration in the medium of 30 μM. However, further incubation for 3 h in the medium without the ketosterol led to restoration of the level of biosynthesis to 85 ± 11% of the control value. These results suggest that inhibition of the cholesterol biosynthesis by 15-ketocholesterol in Hep G2 cells depends on the intracellular concentration of the inhibitor, which, in turn, is determined by the rate of its conversion into the polar metabolite.

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