7 alpha-Hydroxylation of 25-hydroxycholesterol and 27-hydroxycholesterol in human fibroblasts.
The metabolism of 27-hydroxycholesterol and 25-hydroxycholesterol was studied in cultures of human diploid fibroblasts. Both steroids underwent 7 alpha-hydroxylation with subsequent oxidation to 7 alpha-hydroxy-3-oxo-delta 4 steroids. A minor fraction of the 27-hydroxysteroids was oxidized to acids. Competition experiments indicated that both hydroxycholesterols were hydroxylated by the same enzyme, different from cholesterol 7 alpha-hydroxylase. 7 alpha,25-Dihydroxycholesterol suppressed the activity of HMG-CoA reductase at least as effectively as 25-hydroxycholesterol whereas 7 alpha,25-dihydroxy-4-cholesten-3-one was a less effective suppressor. The results suggest that cholesterol might be converted to 7 alpha-hydroxylated bile acid precursors in extrahepatic tissues in vivo and that the regulation of the activity of HMG-CoA reductase by oxysterols might be modulated by 7 alpha-hydroxylation and subsequent oxidation by 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase.
Zhang
J
J
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Larsson
O
O
Sjövall
J
J
D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D006900:Hydroxylation; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D010084:Oxidation-Reduction; D013379:Substrate Specificity
D006888:Hydroxycholesterols; C076996:27-hydroxycholesterol; C007997:25-hydroxycholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase