title: Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2-/- mice.
abstract: 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.
authors.affiliation: Laboratory of Experimental and Molecular Hepatology, Department of Gastroenterology and Hepatology, University Clinic of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Emina
authors.initials: E
authors.lastname: Halilbasic
authors.forename: Romina
authors.initials: R
authors.lastname: Fiorotto
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.forename: Hanns-Ulrich
authors.initials: HU
authors.lastname: Marschall
authors.forename: Tarek
authors.initials: T
authors.lastname: Moustafa
authors.forename: Carlo
authors.initials: C
authors.lastname: Spirli
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuchsbichler
authors.forename: Judith
authors.initials: J
authors.lastname: Gumhold
authors.forename: Dagmar
authors.initials: D
authors.lastname: Silbert
authors.forename: Kurt
authors.initials: K
authors.lastname: Zatloukal
authors.forename: Cord
authors.initials: C
authors.lastname: Langner
authors.forename: Uday
authors.initials: U
authors.lastname: Maitra
authors.forename: Helmut
authors.initials: H
authors.lastname: Denk
authors.forename: Alan F
authors.initials: AF
authors.lastname: Hofmann
authors.forename: Mario
authors.initials: M
authors.lastname: Strazzabosco
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
mesh_terms: 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
chemical_list: D014580:Ursodeoxycholic Acid; C081331:24-norursodeoxycholic acid