title: Cholesterol is converted to 7 alpha-hydroxy-3-oxo-4-cholestenoic acid in liver mitochondria. Evidence for a mitochondrial sterol 7 alpha-hydroxylase.
abstract: The metabolism of cholesterol in isolated intact pig liver mitochondria has been investigated. Six major cholesterol metabolites were identified by gas-liquid chromatography-mass spectrometry, the metabolic end product being 7 alpha-hydroxy-3-oxo-4-cholestenoic acid. Incubations with the synthesized intermediates suggested that the major pathway from cholesterol to this acid proceeds via the sequence of 26-hydroxylation, 7 alpha-hydroxylation, further oxidation of the side chain and oxidation/isomerization in the A-ring. The observed reactions prove that in addition to a sterol 26-hydroxylase, pig liver mitochondria contain significant amounts of a 7 alpha-hydroxylase active on side chain oxygenated 3 beta-hydroxy-delta 5-C27 steroids, an oxidoreductase active in the side chain of 26-hydroxylated steroids and a 3 beta-hydroxy-delta 5 steroid oxidoreductase active on 7 alpha-hydroxylated C27 steroids. Since 7 alpha-hydroxy-3-oxo-4-cholestenoic acid is believed to be an important precursor of chenodeoxycholic acid, this study shows that the first reactions in the biosynthesis of bile acids can be exclusively mitochondrial and thereby bypass microsomal cholesterol 7 alpha-hydroxylase as the rate-limiting enzyme.
authors.affiliation: Department of Clinical Chemistry, Karolinska Hospital, Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Axelson
authors.forename: J
authors.initials: J
authors.lastname: Shoda
authors.forename: J
authors.initials: J
authors.lastname: Sjövall
authors.forename: A
authors.initials: A
authors.lastname: Toll
authors.forename: K
authors.initials: K
authors.lastname: Wikvall
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D002783:Cholestenones / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism*; D015394:Molecular Structure; D009919:Orchiectomy; D013250:Steroid Hydroxylases / Q000378:metabolism*; D013379:Substrate Specificity; D013552:Swine
chemical_list: D002783:Cholestenones; C056891:7 alpha-hydroxy-3-oxo-4-cholestenoic acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C029009:steroid hormone 7-alpha-hydroxylase