Degradation of 24S-hydroxycholesterol in men is not regulated by CYP7A1.
OBJECTIVE
The conversion of cholesterol into bile acids occurs via a long cascade of enzymatically regulated oxidative processes. Our aim was to examine if an up-regulation of hepatic cholesterol 7alpha-hydroxylase (CYP7A1) in humans by cholestyramine, a bile acid-binding resin, has an effect on the degradation of brain-specific 24S-hydroxycholesterol.


METHODS
Six normocholesterolemic male volunteers received 4 g cholestyramine b.i.d. for 2 weeks in an open, prospective exploratory trial. Serum concentrations of lipoproteins and triglycerides were measured by routine enzymatic assays. Sterols and oxysterols were measured by gas chromatography/mass spectrometry.


RESULTS
Total and LDL-cholesterol decreased on the average by 9.3% (p = 0.002) and 19.8% (p = 0.001) after 2 weeks of treatment, respectively. Absolute serum concentrations of 7alpha-hydroxycholesterol, a marker for bile acid production, increased 4-fold after 2 weeks, while 24S- and 27-hydroxycholesterol remained unchanged. Treatment with cholestyramine elevated serum levels of lathosterol, an indicator for the endogenous synthesis of cholesterol, by 146% (p = 0.009).


CONCLUSIONS
In addition to lowering serum concentrations of total cholesterol and LDL-cholesterol, cholestyramine at a dose rate of 4 g b.i.d. causes a significant increase in the CYP7A1 catalyzed 7alpha-hydroxylation of cholesterol and an up-regulation of endogenous cholesterol synthesis, as proven indirectly by an increase in serum lathosterol levels. Total serum levels of 24S- and 27-hydroxycholesterol remained unchanged indicating that an up-regulation in CYP7A1 activity is not responsible for the subsequent oxidative degradation of these hydroxylated sterols.
Knabe
C
C
Department of Clinical Pharmacology, University of Bonn, Germany.
Sudhop
T
T
von Bergmann
K
K
Lütjohann
D
D
D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002792:Cholestyramine Resin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002849:Chromatography, Gas / Q000379:methods; D005410:Flame Ionization / Q000379:methods; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006888:Hydroxycholesterols; D014280:Triglycerides; D002792:Cholestyramine Resin; C044563:24-hydroxycholesterol; C011724:cholest-5-en-3 beta,7 alpha-diol; C001521:lathosterol; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase