title: Metabolism of 4 beta -hydroxycholesterol in humans.
abstract: 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.
authors.affiliation: Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Huddinge, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Bodin
authors.forename: Ulla
authors.initials: U
authors.lastname: Andersson
authors.forename: Eva
authors.initials: E
authors.lastname: Rystedt
authors.forename: Ewa
authors.initials: E
authors.lastname: Ellis
authors.forename: Maria
authors.initials: M
authors.lastname: Norlin
authors.forename: Irina
authors.initials: I
authors.lastname: Pikuleva
authors.forename: Gösta
authors.initials: G
authors.lastname: Eggertsen
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Ulf
authors.initials: U
authors.lastname: Diczfalusy
mesh_terms: D001647:Bile Acids and Salts / Q000737:chemistry; D002460:Cell Line; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D006888:Hydroxycholesterols / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007668:Kidney; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D006888:Hydroxycholesterols; D011994:Recombinant Proteins; C099828:cholest-5-ene-3,4-diol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A