Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2-/- mice.
24-norursodeoxycholic acid (norUDCA), a side chain-modified ursodeoxycholic acid derivative, has dramatic therapeutic effects in experimental cholestasis and may be a promising agent for the treatment of cholestatic liver diseases. We aimed to better understand the physiologic and therapeutic properties of norUDCA and to test if they are related to its side chain length and/or relative resistance to amidation. For this purpose, Mdr2(-/-) mice, a model for sclerosing cholangitis, received either a standard diet or a norUDCA-, tauro norursodeoxycholic acid (tauro- norUDCA)-, or di norursodeoxycholic acid (di norUDCA)-enriched diet. Bile composition, serum biochemistry, liver histology, fibrosis, and expression of key detoxification and transport systems were investigated. Direct choleretic effects were addressed in isolated bile duct units. The role of Cftr for norUDCA-induced choleresis was explored in Cftr(-/-) mice. norUDCA had pharmacologic features that were not shared by its derivatives, including the increase in hepatic and serum bile acid levels and a strong stimulation of biliary HCO(3)(-)-output. norUDCA directly stimulated fluid secretion in isolated bile duct units in a HCO(3)(-)-dependent fashion to a higher extent than the other bile acids. Notably, the norUDCA significantly stimulated HCO(3)(-)-output also in Cftr(-/-) mice. In Mdr2(-/-) mice, cholangitis and fibrosis strongly improved with norUDCA, remained unchanged with tauro- norUDCA, and worsened with di norUDCA. Expression of Mrp4, Cyp2b10, and Sult2a1 was increased by norUDCA and di norUDCA, but was unaffected by tauro- norUDCA.


CONCLUSIONS
The relative resistance of norUDCA to amidation may explain its unique physiologic and pharmacologic properties. These include the ability to undergo cholehepatic shunting and to directly stimulate cholangiocyte secretion, both resulting in a HCO(3)(-)-rich hypercholeresis that protects the liver from cholestatic injury.
Halilbasic
Emina
E
Laboratory of Experimental and Molecular Hepatology, Department of Gastroenterology and Hepatology, University Clinic of Internal Medicine, Medical University of Graz, Graz, Austria.
Fiorotto
Romina
R
Fickert
Peter
P
Marschall
Hanns-Ulrich
HU
Moustafa
Tarek
T
Spirli
Carlo
C
Fuchsbichler
Andrea
A
Gumhold
Judith
J
Silbert
Dagmar
D
Zatloukal
Kurt
K
Langner
Cord
C
Maitra
Uday
U
Denk
Helmut
H
Hofmann
Alan F
AF
Strazzabosco
Mario
M
Trauner
Michael
M
D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000517:prevention & control*; D008297:Male; D051379:Mice; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
D014580:Ursodeoxycholic Acid; C081331:24-norursodeoxycholic acid