24,25-Epoxysterol metabolism in cultured mammalian cells and repression of 3-hydroxy-3-methylglutaryl-CoA reductase.
In view of the potential importance of 24,25-epoxysterols as intracellular regulators of 3-hydroxy-3-methylglutaryl-CoA reductase, the C-24 epimers of 24,25-oxidolanosterol and 24,25-epoxycholesterol were tested for their biological activity and metabolism in cell cultures. All four compounds produced repression of the reductase in cultured mouse fibroblasts (L cells), and both 24(S)- and 24(R),25-epoxycholesterol exhibited high affinity binding to the cytosolic oxysterol-binding protein. However, binding of the epimeric 24,25-oxidolanosterols was not detected. 24(S),25-Epoxycholesterol was not rapidly metabolized in either L cells or Chinese hamster lung (Dede) cells. 24(S),25-Oxidolanosterol was rapidly converted to 24(S),25-epoxycholesterol in both cell lines. 24(R),25-Oxidolanosterol was converted to 24(R)-hydroxycholesterol in Dede cells, but was converted instead to 24(R),25-epoxycholesterol in L cells, which lack sterol delta 24-reductase activity. Although 24(S),25-oxidolanosterol does not appear to accumulate in these cell cultures, it was found in human liver in about one-fifth the amount of 24(S),25-epoxycholesterol. 24(R),25-Epoxycholesterol was also converted to 24(R)-hydroxycholesterol in Dede cells, but not in L cells. Triparanol inhibited the reduction of the 24(R),25-epoxides in Dede cells, consistent with the idea that this reaction is catalyzed by the delta 24-reductase. 24(R)-Hydroxycholesterol and its 24(S) epimer exhibited affinity for the binding protein and repressed 3-hydroxy-3-methylglutaryl-CoA reductase.
D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004794:Enzyme Repression; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D007739:L Cells / Q000201:enzymology; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D051379:Mice; D014316:Tritium
D014316:Tritium; C015410:24,25-oxidolanosterol; D007810:Lanosterol; C028358:24,25-epoxycholesterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases