Use of cholesterol precursors to assess changes in cholesterol synthesis under non-steady-state conditions.
BACKGROUND
Quantification of plasma levels of an early and late intermediate on the cholesterol pathway, mevalonic acid (MVA) and lathosterol respectively, provides a useful method of estimating cholesterol synthesis in humans. The aim of this study was to assess further their roles as indices of cholesterol synthesis under non-steady-state conditions.


METHODS
The short-term effects of pharmacological inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase on both variables were determined in four normolipidaemic subjects during and after treatment with simvastatin 20 mg daily. Plasma MVA was measured using gas chromatography-mass spectrometry, and lathosterol using gas chromatography.


RESULTS
A single dose of 20 mg of simvastatin decreased plasma MVA after 2 h and decreased the lathosterol-cholesterol (L/C) ratio after 4 h. Treatment with simvastatin 20 mg daily for 9 days decreased both variables by approximately 50%, the nadir of plasma MVA occurring on the second day and of the L/C ratio on the fifth day, and resulted in a 39% reduction in low-density lipoprotein (LDL)-cholesterol. After discontinuing simvastatin, there were rebounds in plasma MVA and the L/C ratio to above basal levels but not in LDL cholesterol or apolipoprotein B (apoB), the latter continuing to decrease for a further 2 days.


CONCLUSIONS
These results suggest that simvastatin rapidly down-regulates cholesterol synthesis, which is then up-regulated when the drug is withdrawn.
Pfohl
M
M
Eberhard-Karls-Universität Tübingen, Medizinische Klinik und Poliklinik, Tübingen, Germany.
Naoumova
R P
RP
Kim
K D
KD
Thompson
G R
GR
D000214:Acyl Coenzyme A / Q000378:metabolism; D000328:Adult; D000704:Analysis of Variance; D000924:Anticholesteremic Agents / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008297:Male; D015093:Meglutol / Q000378:metabolism; D008798:Mevalonic Acid / Q000097:blood*; D019821:Simvastatin / Q000494:pharmacology
D000214:Acyl Coenzyme A; D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; C001521:lathosterol; D002784:Cholesterol; D019821:Simvastatin; D015093:Meglutol; D008798:Mevalonic Acid