Early morphologic and enzymatic changes in livers of rats treated with chenodeoxycholic and ursodeoxycholic acids

Abstract

The effect of high doses of chenodeoxycholic and ursodeoxycholic acids on hepatic morphology and on cholesterol and bile acid metabolism was examined in the rat. After 2 weeks of either cheno or ursodeoxycholic acid feeding, the livers of the treated rats revealed marked proliferation of the smooth endoplasmic reticulum which appeared as an adaptation phenomenon of the microsomal enzyme system in response to bile acid intake. However, the livers of the chenodeoxycholic acid-treated rats showed early alteration that included mild triaditis, swelling of the bile canalicular microvilli, distended Golgi vesicles, whorling of the mitochondria, and presence of large vacuoles bound by single membranes. During cheno- or ursodeoxycholic acid treatment, the administered bile acid predominated in the bile and amounted to 79 or 67% of the biliary bile acids, respectively. At the same time, the concentration of the muricholic acids was also increased. Biliary cholic acid content dropped significantly, but no change in lithocholic acid concentration was observed. In addition, the activity of HMG-CoA reductase as well as that of cholesterol-7 alpha-hydroxylase was reduced by either of the administered bile acids, while no change in hepatic cholesterol content was detected, and intestinal cholesterol absorption was not significantly different from that of controls. These results show that cheno- and ursodeoxycholic acids inhibited hepatic cholesterol and bile acid synthesis but did not increase either intestinal cholesterol absorption or hepatic microsomal cholesterol content. Since the amounts of biliary lithocholic acid were similar in the bile acid-treated animals, the morphologic abnormalities detected in the chenodeoxycholic acid-fed rats are probably due to an increased pool of chenodeoxycholic acid. However, lithocholic acid-induced liver injury cannot be excluded.