Use of cholesterol precursors to assess changes in cholesterol synthesis under non-steady-state conditions

Eur J Clin Invest. 1998 Jun;28(6):491-6. doi: 10.1046/j.1365-2362.1998.00321.x.

Abstract

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.

Conclusion: These results suggest that simvastatin rapidly down-regulates cholesterol synthesis, which is then up-regulated when the drug is withdrawn.

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Adult
  • Analysis of Variance
  • Anticholesteremic Agents / pharmacology
  • Cholesterol / biosynthesis*
  • Cholesterol / blood*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Male
  • Meglutol / metabolism
  • Mevalonic Acid / blood*
  • Simvastatin / pharmacology

Substances

  • Acyl Coenzyme A
  • Anticholesteremic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • 3-hydroxy-3-methylglutaryl-coenzyme A
  • lathosterol
  • Cholesterol
  • Simvastatin
  • Meglutol
  • Mevalonic Acid