Inhibition of Cholesterol Synthesis Causes Both Hypercholesterolemia and Hypocholesterolemia in Hamsters

Abstract

Effects of FR194738 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[2-methyl-2-(3-thienylmethoxy)propyloxy]benzylamine hydrochloride), a squalene epoxidase inhibitor, on lipid metabolism were compared with those of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in hamsters. Drugs were given for 10 d either as a diet mixture or as a bolus oral gavage, and similar results were obtained with each type of administration. FR194738 (0.01—0.32% as a diet mixture; 10—100 mg/kg as an oral gavage) dose-dependently decreased serum total cholesterol, non high density lipoprotein (HDL) cholesterol, HDL cholesterol and triglyceride levels, and the changes in serum parameters were similar. Pravastatin (0.01—0.32% as a diet mixture; 1—100 mg/kg as an oral gavage) increased serum cholesterol levels, and dose-dependently decreased serum triglyceride levels. Although oral gavage of FR194738 at 32 mg/kg and pravastatin at 3.2 and 10 mg/kg increased hepatic HMG-CoA reductase activity, the degree of the changes was far greater with the latter than the former drug. FR194738 slightly increased hepatic cholesterol content at 32 mg/kg, whereas pravastatin dose-dependently increased hepatic cholesterol content until it leveled off at 32 and 100 mg/kg. It is concluded that inhibition of squalene epoxidase and HMG-CoA reductase triggers both hypercholesterolemic (hepatic cholesterol synthesis) and hypocholesterolemic (hepatic cholesterol uptake) mechanisms. FR194738 appears to induce a greater enhancement of the latter rather than the former, whereas pravastatin has a greater effect on the former.