On the origin of the cholestenoic acids in human circulation.
3 Beta-hydroxy-5-cholestenoic acid, 3 beta,7 alpha-dihydroxy-5-cholestenoic acid, and 7 alpha-hydroxy-3-oxo-4-cholestenoic acid are metabolites of cholesterol present at significant concentrations (40-80 ng/ml) in human circulation. The 7 alpha-hydroxylated acids may be formed from cholesterol via two major pathways initiated by oxidations at either the 7 alpha- or 27-positions. In an attempt to clarify the origin and possible precursor-product relationships between these cholestenoic acids, we measured their deuterium enrichment in a unique experiment, after infusion of 10 g of [2H(6)]-cholesterol to a healthy volunteer. The observed extent and time-course of deuterium enrichment of circulating 3 beta-hydroxy-5-cholestenoic and 3 beta,7 alpha-dihydroxy-5-cholestenoic acid were almost identical, while different from that of cholesterol and 7 alpha-hydroxycholesterol. Notably, the deuterium enrichment of 7 alpha-hydroxy-3-oxo-4-cholestenoic acid was similar to that of 7 alpha-hydroxycholesterol (and its metabolite 7 alpha-hydroxy-4-cholesten-3-one), though distinct from the other cholestenoic acids. Finally, the enrichment of unesterified 27-hydroxycholesterol followed a similar, though less pronounced, time curve to the delta(5)-cholestenoic acids. In conclusion, these results suggest that plasma 3 beta-hydroxy-5-cholestenoic acid is formed from a pool of cholesterol distinct from that used for the formation of the bulk of 27-hydroxycholesterol. The results are also in accordance with a formation of 3 beta,7 alpha-dihydroxy-5-cholestenoic acid directly from 3 beta-hydroxy-5-cholestenoic acid, and a formation of most of the circulating 7 alpha-hydroxy-4-cholesten-3-one from 7 alpha-hydroxycholesterol. These results are consistent with a flux of 7 alpha-hydroxycholesterol from the liver into the circulation, and an extrahepatic metabolism of this steroid into 7 alpha-hydroxy-3-oxo-4-cholestenoic acid.
Meaney
Steve
S
Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Stockholm, Sweden.
Babiker
Amir
A
Lütjohann
Dieter
D
Diczfalusy
Ulf
U
Axelson
Magnus
M
Björkhem
Ingemar
I
D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism; D002782:Cholestenes / Q000097:blood / Q000378:metabolism*; D002783:Cholestenones / Q000097:blood / Q000378:metabolism; D002784:Cholesterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D003903:Deuterium / Q000008:administration & dosage; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged
D001647:Bile Acids and Salts; D002782:Cholestenes; D002783:Cholestenones; D006888:Hydroxycholesterols; C063075:3,7-dihydroxy-5-cholestenoic acid; C056891:7 alpha-hydroxy-3-oxo-4-cholestenoic acid; C011724:cholest-5-en-3 beta,7 alpha-diol; C029435:3-hydroxy-5-cholestenoic acid; C076996:27-hydroxycholesterol; D002784:Cholesterol; D003903:Deuterium