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.
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.
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D002994:Clofibrate / Q000494:pharmacology; D004072:Digitonin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013261:Sterols / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D008055:Lipids; D013261:Sterols; D010649:Phenylalanine; C034166:N-(4-methylbenzylthiocarbonyl)phenylalanine; D002784:Cholesterol; D002994:Clofibrate; D004072:Digitonin