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7 alpha-hydroxylation of 27-hydroxycholesterol: biologic role in the regulation of cholesterol synthesis.

Title7 alpha-hydroxylation of 27-hydroxycholesterol: biologic role in the regulation of cholesterol synthesis.
Publication TypeJournal Article
Year of Publication1997
AuthorsMartin KO, Reiss AB, Lathe R, Javitt NB
JournalJ Lipid Res
Volume38
Issue5
Pagination1053-8
Date Published1997 May
ISSN0022-2275
KeywordsAnimals, CHO Cells, Cholesterol, Cricetinae, Cytochrome P-450 Enzyme System, Hydroxycholesterols, Hydroxylation, Mice, Steroid Hydroxylases, Substrate Specificity
Abstract

The report of a novel cytochrome P450 enzyme in mouse hippocampus (cyp7b) with close homology to cholesterol 7 alpha-hydroxylase led us to determine the substrate specificity with respect to 27-hydroxycholesterol, known to be a potent inhibitor of cholesterol synthesis. Transfection of 293/T-cells with PcDNA3.1(+)-mcyp7b was followed by metabolism of 2.5 microM 27-hydroxycholesterol to the 7 alpha-hydroxy intermediate, cholest-5-ene,3 beta,7 alpha,27-triol, with complete loss of down-regulation of cholesterol synthesis. Addition of 5 microM and 10 microM concentrations of the triol to HepG2 and CHO cells, respectively, also did not reduce cholesterol synthesis. The contrast between the biologic effect on cholesterol synthesis by these two C27 hydroxysterols and the wide tissue distribution of both cholesterol 27-hydroxylase and hydroxysterol 7 alpha-hydroxylase implies local regulatory effects prior to their further catabolism in the liver to chenodeoxycholic and cholic acids.

Alternate JournalJ. Lipid Res.
PubMed ID9186922
Grant ListDK 32995 / DK / NIDDK NIH HHS / United States