Effect of FR194738, a potent inhibitor of squalene epoxidase, on cholesterol metabolism in HepG2 cells.

Abstract

(E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-methyl-2-(3-thienylmethoxy)propyloxy]benzylamine hydrochloride (FR194738) inhibited squalene epoxidase activity in HepG2 cell homogenates with an IC50 value of 9.8 nM. In the study using intact HepG2 cells, FR194738 inhibited cholesterol synthesis from [14C]acetate with an IC50 value of 4.9 nM, and induced intracellular [14C]squalene accumulation. On the other hand, the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor simvastatin reduced both cholesterol and squalene synthesis from [14C]acetate. Incubation with simvastatin for 18 h produced increases in HMG-CoA reductase activity in HepG2 cells, which was related to the degree of reduction in cholesterol synthesis. The HMG-CoA reductase activity increased by 13- and 19-fold at the concentrations of simvastatin that inhibited cholesterol synthesis by 65% and 82%, respectively. In contrast, FR194738 did not increase HMG-CoA reductase activity at the concentrations that inhibited cholesterol synthesis by 24% and 69%, and moderate increase (4.6-fold) was observed at the concentration that inhibited cholesterol synthesis by 90%. These results suggest that non-sterol metabolite(s) derived from mevalonate prior to the squalene epoxidation step in the cholesterol synthetic cascade have a regulatory role in the suppression of HMG-CoA reductase activity. We speculate that FR194738 inhibits cholesterol synthesis with a minimal change of the regulator(s) and would be highly effective in the treatment of hypercholesterolemia.

• Authors: M Sawada, M Matsuo, H Hagihara, N Tenda, A Nagayoshi, H Okumura, K Washizuka, J Seki, T Goto
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 431 Issue 1 Pg. 11-6 (Nov 09 2001) ISSN: 0014-2999 [Print] Netherlands
• PMID: 11716837 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Benzylamines
• Enzyme Inhibitors
• FR 194738
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Squalene
• Cholesterol
• simvastatin acid
• Simvastatin
• Hydroxymethylglutaryl CoA Reductases
• Oxygenases
• Squalene Monooxygenase

Topics

• Benzylamines (pharmacology)
• Cholesterol (biosynthesis, metabolism)
• Enzyme Inhibitors (pharmacology)
• Humans
• Hydroxymethylglutaryl CoA Reductases (isolation & purification, metabolism)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Molecular Structure
• Oxygenases (antagonists & inhibitors)
• Simvastatin (analogs & derivatives, pharmacology)
• Squalene (metabolism)
• Squalene Monooxygenase
• Tumor Cells, Cultured