Mode of action of terbufibrol (INN) a hypolipidemic agent on rat liver sterol synthesis.
In an in vitro assay, rat liver cholesterol synthesis from acetate (14C-labelled) was inhibited by the hypolipidemic compound Terbufibrol (6, 11). In contrast to this, Terbufibrol in the same concentration showed hardly any effect on cholesterol synthesis with HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) and mevalonate as precursors. However, liver cytosols of rats pretreated with Terbufibrol (100 mg/kg), showed in vitro double cholesterol synthesis with the precursors acetate and HMG-CoA and practically no effect with mevalonate compared to controls. This stimulating effect of Terbufibrol on sterol synthesis was observed during the basal period as well as at the maximum during the diurnal rhythm of that metabolic pathway. With the help of inhibitors of protein (Cycloheximide) and RNA (Actinomycin D) synthesis it was shown that the stimulating effect of Terbufibrol on liver cholesterol synthesis was dependent on de novo protein synthesis. Further it was observed that the hepatic cholesterol 7 alpha-hydroxylase reaction was inhibited in a dose related fashion after pretreatment with Terbufibrol. From our results it was concluded that Terbufibrol blocks the hepatic cholesterol synthesis in a step between acetate and HMG-CoA.
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D002940:Circadian Rhythm / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013261:Sterols / Q000096:biosynthesis*; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D001565:Benzoates; D013261:Sterols; D014280:Triglycerides; D003609:Dactinomycin; D002784:Cholesterol; D003513:Cycloheximide; D006899:Mixed Function Oxygenases; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid; C020508:terbufibrol