TY - JOUR
T1 - Differing effects of nor-ursodeoxycholic or ursodeoxycholic acid on hepatic histology and bile acid metabolism in the rabbit
AU - Cohen, Bertram I.
AU - Hofmann, Alan F.
AU - Mosbach, Erwin H.
AU - Stenger, Richard J.
AU - Rothschild, Marcus A.
AU - Hagey, Lee R.
AU - Yoon, Yong Bum
N1 - Funding Information:
Received November 22, 1985. Accepted January 27, 1986. Address requests for reprints to: Bertram I. Cohen, Ph.D., Department of Surgery, Beth Israel Medical Center, First Avenue at 16th Street, New York, New York 10003. This work was supported in part by United States Public Health Service grants AM 21506 and AM 32130 (A.F.H.) and HL 24061 (E.H.M.) from the National Institutes of Health. Mass spectrometric analysis was performed at the Mass Spectrometry Facility, School of Pharmacy, University of California, San Francisco, which is supported by a Biotechnology Resources Grant, Division of Research Resources, RR 01614. 0 1986 by the American Gastroenterological 0016-5085/86/$3.50
PY - 1986/7
Y1 - 1986/7
N2 - 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. Norursodeoxycholate 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 norursodeoxycholate 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.
AB - 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. Norursodeoxycholate 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 norursodeoxycholate 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.
UR - http://www.scopus.com/inward/record.url?scp=0022481962&partnerID=8YFLogxK
U2 - 10.1016/0016-5085(86)90457-9
DO - 10.1016/0016-5085(86)90457-9
M3 - Article
C2 - 3710068
AN - SCOPUS:0022481962
SN - 0016-5085
VL - 91
SP - 189
EP - 197
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -