Effect of mevinolin on cholesterol metabolism in obese and lean Zucker rats

Mevinolin is a potent competitive inhibitor of HMG-CoA reductase, the enzyme catalyzing the major rate-limiting step in cholesterol synthesis. In this study the drug was administered as an intragastric dose at 2.5 mg/kg/day to 10 to 12-week-old lean and obese Zucker female rats over a 5-day period. Mevinolin showed no effect on plasma cholesterol levels in the lean rat; however, in the obese rat there was a significant decrease in plasma cholesterol (about a 40% decrease from initial levels). Although there was a difference in effect on plasma cholesterol levels in obese and lean rats, hepatocytes isolated from both fed lean and obese rats incubated with various concentrations of mevinolin exhibited similar levels of inhibition of cholesterol synthesis and showed no effects on the other metabolic processes studied. These results indicate that the drug was effective acutely on cholesterol synthesis in hepatocytes isolated from both lean and obese rats, but on a chronic treatment basis the hypocholesterolemic effect was observed only in the obese Zucker rat. This study supports the idea that the naturally occurring hypercholesterolemic obese Zucker rat may be a good model for testing potential new cholesterol lowering agents.