Differing effects of nor-ursodeoxycholic or ursodeoxycholic acid on hepatic histology and bile acid metabolism in the rabbit

Abstract

Nor-ursodeoxycholate, the C23 analogue of ursodeoxycholate, is a potent choleretic agent in rodents when given acutely but, to be used in humans, chronic toxicity studies are required. In the rabbit, ingestion of ursodeoxycholate or chenodeoxycholate leads to accumulation of lithocholate, its major bacterial metabolite, in biliary bile acids, which causes inflammation in portal tracts of the liver and bile duct proliferation. To test whether chronic administration of nor-ursodeoxycholate would cause an analogous accumulation of nor-lithocholate and hepatotoxicity, rabbits were fed a Chow diet containing nor-ursodeoxycholate (5 or 50 mg/day): control groups received Chow alone, and "disease control" groups received Chow plus ursodeoxycholate or Chow plus chenodeoxycholate. After 3 wk, animals were killed, liver sections were interpreted by a pathologist, and the steroid moiety of the glycine (and taurine) conjugates of gallbladder bile acids were analyzed by high-pressure liquid chromatography. Ingestion of nor-ursodeoxycholate did not cause hepatotoxicity, and neither it nor its presumed metabolite, nor-lithocholate, accumulated in biliary bile acids. To explain this unexpected finding, the hepatic metabolism of nor-ursodeoxycholate was investigated in biliary fistula rabbits. Nor-ursodeoxycholate was well absorbed from the intestine and secreted in the bile as a glucuronide as well as the unchanged compound, but conjugation with glycine and taurine was not observed. As glucuronides are poorly absorbed from the gut, it is proposed that the hepatic biotransformation of nor-ursodeoxycholate to a glucuronide rather than to a glycine amidate in the liver prevented its accumulation in the bile acid pool. Thus, shortening the side chain of ursodeoxycholate by a single carbon atom resulted in a bile acid with novel metabolism, which when administered chronically, does not accumulate in the enterohepatic circulation and does not cause hepatotoxicity.