From brain to bile. Evidence that conjugation and omega-hydroxylation are important for elimination of 24S-hydroxycholesterol (cerebrosterol) in humans.
The brain is the almost exclusive site of formation of 24S-hydroxycholesterol in man, and there is a continuous flux of this oxysterol across the blood-brain barrier into the circulation. The hepatic metabolism of 24S-hydroxycholesterol was studied here by three different approaches: incubation of tritium-labeled 24S-hydroxycholesterol with human primary hepatocytes, administration of tritium-labeled 24S-hydroxycholesterol to a human volunteer, and quantitation of free and conjugated 24S-hydroxycholesterol and its neutral metabolites in ileocecal fluid from patients with ileal fistulae. 24S-Hydroxycholesterol as well as 24R-hydroxycholesterol were converted into bile acids by human hepatocytes at a rate of about 40% of that of the normal intermediate in bile acid synthesis, 7 alpha-hydroxycholesterol. There was also a conversion of 24S-hydroxycholesterol into conjugate(s) of 5-cholestene-3 beta,24S,27-triol at a rate similar to the that of conversion into bile acids. When administered to a human volunteer, labeled 24S-hydroxycholesterol was converted into bile acids at about half the rate of simultaneously administered labeled 7 alpha-hydroxycholesterol. Free, sulfated, and glucuronidated 24S-hydroxycholesterol and 5-cholestene-3 beta,24,27-triol were identified in ileocecal fluid. The excretion of these steroids was about 3.5 mg/24 h, amounting to more than 50% of the total estimated flux of 24S-hydroxycholesterol from the brain. It is concluded that 24S-hydroxycholesterol is a less efficient precursor to bile acids and that about half of it is conjugated and eliminated in bile as such or as a conjugate of a 27-hydroxylated metabolite. The less efficient metabolism of 24S-hydroxycholesterol may explain the surprisingly high levels of this oxysterol in the circulation and is of interest in relation to the suggested role of 24S-hydroxycholesterol as a regulator of cholesterol homeostasis.
Bjorkhem
I
I
Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, S-141 86 Huddinge, Sweden. Ingemar.Bjorkhem@chemlab.hs.sll.se
Andersson
U
U
Ellis
E
E
Alvelius
G
G
Ellegard
L
L
Diczfalusy
U
U
Sjovall
J
J
Einarsson
C
C
D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002782:Cholestenes / Q000302:isolation & purification; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism*; D006900:Hydroxylation; D007080:Ileocecal Valve / Q000378:metabolism; D014316:Tritium
D001647:Bile Acids and Salts; D002782:Cholestenes; D006888:Hydroxycholesterols; C438385:cholestene-3,24,27-triol; D014316:Tritium; C044563:24-hydroxycholesterol