Effects of n-(4-methylbenzylthiocarbonyl)-l-phenylalanine (kf 1492), a new phenylalanine derivative, on lipid synthesis in vivo inhibition of hepatic cholesterol synthesis and 3-hydroxy-3-methylglutaryl-Co a reductase.

Abstract

KF 1492, a new phenylalanine derivative, was administered at a dose of 100 mg/kg or 0.25% (w/w) diet to Wistar rats. After different periods of drug administration, incorporation of 14 C-acetate or 14 C-mevalonic acid into digitonin-precipitable sterols and hepatic 3-hydroxy-3-methylglutaryl-Co A (HMG-CoA) reductase activity were measured. KF 1492 feeding was associated with depressed incorporation of 14 C-acetate into sterols in liver slices or homogenate. There was no effect on incorporation of 14 C-mevalonic acid into sterols. Thus, KF 1492 administration induced inhibition of hepatic HMG-CoA reductase correlated with reduction of incorporation of 14 C-acetate into digitonin-precipitable sterols. KF 1492 feeding also inhibited in vivo sterol synthesis in rats, which was intraperitoneally injected with 14 C-acetate. Stereoisomers, metabolites adn chemically similar compounds of KF 1492 reduced HMG-CoA reductase activity, and this was correlated with lowering the activity of plasma cholesterol. These findings indicate that a major site of the action of KF 1492 in the inhibition of sterol synthesis may be at the level of HMG-CoA reductase.