Comparative effects of ursodeoxycholic acid and chenodeoxycholic acid in the rhesus monkey

Abstract To investigate the effects of bile acid feeding on hepatic function, rhesus monkeys were treated with 40 and 100 mg per kg per day of ursodeoxycholic acid (UDCA) (3α,7β-dihydroxycholanoic acid) and chenodeoxycholic acid (CDCA) (3α,7α-dihydroxycholanoic acid), respectively. Serum transaminases (SGOT, SGPT) and leucine aminopeptidase levels were measured at the start of the studies, at monthly intervals thereafter, and terminally. After six months, all animals were killed and hepatic morphology was examined by light and electron microscopy; biliary bile acid composition and fecal bile composition were determined by gas-liquid chromatography. Liver damage developed in the CDCA-treated animals and consisted of bile duct proliferation, periportal inflammation, fibrosis and disruption of bile canaliculi, and was associated with a 4- to 10-fold rise in serum transaminase and leucine aminopeptidase levels. Biliary lithocholic acid rose to 10% of the total biliary bile acids in the CDCA-treated animals. In contrast, liver morphology and function tests were not affected by either 40 or 100 mg per kg per day of UDCA; biliary lithocholic acid concentrations did not change appreciably. Hepatic β-hydroxy-β-methylglutaryl coenzme A reductase activity reflecting cholesterogenesis was suppressed equally (30%) by UDCA and CDCA, but serum cholesterol levels did not change. These findings confirm that CDCA is associated with serious liver damage that probably results from increased formation of lithocholic acid. In contrast, UDCA caused no liver toxicity and no rise in lithocholic acid. Thus, the 7β-hydroxy group of UDCA was apparently degraded differently than the 7α-hydroxy group of CDCA, suggesting that intestinal bacterial dehydroxylases are stereospecific. Because of different bacterial degradation, gallstone treatment with UDCA may be safer and more economical.