The Effect of the Hypocholesteremic Drug, AY 9944 on the Synthesis of Bile Salts in Rat Liver

Abstract

The compound trans-1,4 bis-(2-dichlorobenzylaminomethyl)cyclohexane dihydrochloride (AY9944) blocks cholesterol synthesis at a late stage. This leads to a decrease in cholesterol and accumulation of cholesta-5,7-diene-3.beta.-ol (7-dehydrocholesterol) in tissues and plasma. The effect of AY9944 on bile salt synthesis in rat liver was studied. The synthesis of conjugated cholic and chenodeoxycholic acids was measured in hepatocytes isolated from rats 2, 24 and 48 h after administration of a single oral dose of AY9944. Production of the 2 bile salts was inhibited by 70-80% in hepatocytes from AY9944-treated as compared to untreated animals. When AY9944 was added to the incubation medium in vitro of hepatocytes prepared from untreated rats the synthesis of conjugated cholic and chenodeoxycholic acids was not inhibited during the 1st h of incubation, probably because of the presence of endogenous cholesterol. When hepatocytes from untreated rats were incubated with AY9944 for periods of 2 h or longer, bile salt production was decreased markedly. Bile salt synthesis is stimulated when rats are subjected to total biliary drainage for 24 h. The effect of AY9944 on this stimulation was studied. The content of conjugated cholic and chenodeoxycholic acid in the bile was measured as an indicator of bile salt synthesis. In control animals, the rate of secretion biliary bile salts began to increase after .apprx. 24 h of total biliary drainage and reached a maximum after .apprx. 36 h. A single oral dose of AY9944 given 2 h after the start of total biliary drainage delayed and reduced this response. Inhibition of cholesterol synthesis by AY9944 resulting in the replacement of cholesterol by 7-dehydrocholesterol decreases but does not completely prevent bile salt synthesis.