Studies on the relationships between 7 alpha-hydroxylation and the ability of 25- and 27-hydroxycholesterol to suppress the activity of HMG-CoA reductase.
The metabolism of 25-hydroxycholesterol in different cell types was studied and the role of 7 alpha-hydroxylation for the effect of 25-hydroxycholesterol on the activity of HMG-CoA reductase was determined. Human diploid fibroblasts (HDF) and the human melanoma cell line SK-MEL-2 converted 25-hydroxycholesterol into 7 alpha,25-dihydroxycholesterol and 7 alpha,25-dihydroxy-4-cholesten-3-one while the virus-transformed fibroblast line 90VA-VI, the colon carcinoma cell line WiDr and the breast cancer cell line MDA-231 did not express 7 alpha-hydroxylase activity. The 7 alpha-hydroxylation of 25-hydroxycholesterol in HDF could be stimulated by dexamethasone and cortisol and inhibited by metyrapone. An unidentified, possibly 4-hydroxylated, metabolite was formed by 90VA-VI cells and a polar, probably conjugated, metabolite was formed by WiDr cells. The 7 alpha-hydroxylated metabolites of 25-hydroxycholesterol suppressed the activity of HMG-CoA reductase to a similar extent as 25-hydroxycholesterol in HDF but not in 90VA-VI cells, while the 7 alpha-hydroxylated metabolites of 27-hydroxycholesterol suppressed the activity of HMG-CoA reductase also in 90VA-VI cells. The suppression of HMG-CoA reductase activity by 25- and 27-hydroxycholesterol was decreased or abolished by dehydroepiandrosterone or pregnenolone which have little or no effect on the 7 alpha-hydroxylation. The results indicate that 7 alpha-hydroxylation is not directly involved, positively or negatively, in the action of 25- or 27-hydroxycholesterol as suppressors of HMG-CoA reductase activity.
Zhang
J
J
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Dricu
A
A
Sjövall
J
J
D001189:Aryl Hydrocarbon Hydroxylases; D002460:Cell Line; D002461:Cell Line, Transformed; D002783:Cholestenones / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology*; D006900:Hydroxylation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008797:Metyrapone / Q000494:pharmacology; D011284:Pregnenolone / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000378:metabolism; D014407:Tumor Cells, Cultured
C104752:7,25-dihydroxy-4-cholesten-3-one; D002783:Cholestenones; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C057657:7,25-dihydroxycholesterol; D003687:Dehydroepiandrosterone; C076996:27-hydroxycholesterol; D011284:Pregnenolone; C007997:25-hydroxycholesterol; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C029009:steroid hormone 7-alpha-hydroxylase; D006854:Hydrocortisone; D008797:Metyrapone