Document Detail

Metabolism of 4 beta -hydroxycholesterol in humans.
MedLine Citation:
PMID:  12077124     Owner:  NLM     Status:  MEDLINE    
One of the major oxysterols in the human circulation is 4 beta-hydroxycholesterol formed from cholesterol by the drug-metabolizing enzyme cytochrome P450 3A4. Deuterium-labeled 4 beta-hydroxycholesterol was injected into two healthy volunteers, and the apparent half-life was found to be 64 and 60 h, respectively. We have determined earlier the half-lives for 7 alpha-, 27-, and 24-hydroxycholesterol to be approximately 0.5, 0.75, and 14 h, respectively. Patients treated with certain antiepileptic drugs have up to 20-fold increased plasma concentrations of 4 beta-hydroxycholesterol. The apparent half-life of deuterium-labeled 4 beta-hydroxycholesterol in such a patient was found to be 52 h, suggesting that the high plasma concentration was because of increased synthesis rather than impaired clearance. 4 beta-Hydroxycholesterol was converted into acidic products at a much slower rate than 7 alpha-hydroxycholesterol in primary human hepatocytes, and 4 beta-hydroxycholesterol was 7 alpha-hydroxylated at a slower rate than cholesterol by recombinant human CYP7A1. CYP7B1 and CYP39A1 had no activity toward 4 beta-hydroxycholesterol. These results suggest that the high plasma concentration of 4 beta-hydroxycholesterol is because of its exceptionally slow elimination, probably in part because of the low rate of 7 alpha-hydroxylation of the steroid. The findings are discussed in relation to a potential role of 4 beta-hydroxycholesterol as a ligand for the nuclear receptor LXR.
Karl Bodin; Ulla Andersson; Eva Rystedt; Ewa Ellis; Maria Norlin; Irina Pikuleva; Gösta Eggertsen; Ingemar Björkhem; Ulf Diczfalusy
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2002-06-20
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Aug 
Date Detail:
Created Date:  2002-08-30     Completed Date:  2002-10-17     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  31534-40     Citation Subset:  IM    
Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Huddinge, Sweden.
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MeSH Terms
Bile Acids and Salts / chemistry
Cell Line
Cells, Cultured
Cytochrome P-450 Enzyme System / metabolism
Hepatocytes / metabolism*
Hydroxycholesterols / administration & dosage,  metabolism,  pharmacokinetics*
Infusions, Intravenous
Mass Spectrometry
Metabolic Clearance Rate
Mixed Function Oxygenases / metabolism
Recombinant Proteins / metabolism
Grant Support
Reg. No./Substance:
0/Bile Acids and Salts; 0/Hydroxycholesterols; 0/Recombinant Proteins; 17320-10-4/cholest-5-ene-3,4-diol; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC protein, human

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