title: Defective canalicular transport and toxicity of dietary ursodeoxycholic acid in the abcb11-/- mouse: transport and gene expression studies.
abstract: The bile salt export pump (BSEP), encoded by the abcb11 gene, is the major canalicular transporter of bile acids from the hepatocyte. BSEP malfunction in humans causes bile acid retention and progressive liver injury, ultimately leading to end-stage liver failure. The natural, hydrophilic, bile acid ursodeoxycholic acid (UDCA) is efficacious in the treatment of cholestatic conditions, such as primary biliary cirrhosis and cholestasis of pregnancy. The beneficial effects of UDCA include promoting bile flow, reducing hepatic inflammation, preventing apoptosis, and maintaining mitochondrial integrity in hepatocytes. However, the role of BSEP in mediating UDCA efficacy is not known. Here, we used abcb11 knockout mice (abcb11-/-) to test the effects of acute and chronic UDCA administration on biliary secretion, bile acid composition, liver histology, and liver gene expression. Acutely infused UDCA, or its taurine conjugate (TUDC), was taken up by the liver but retained, with negligible biliary output, in abcb11-/- mice. Feeding UDCA to abcb11-/- mice led to weight loss, retention of bile acids, elevated liver enzymes, and histological damage to the liver. Semiquantitative RT-PCR showed that genes encoding Mdr1a and Mdr1b (canalicular) as well as Mrp4 (basolateral) transporters were upregulated in abcb11-/- mice. We concluded that infusion of UDCA and TUDC failed to induce bile flow in abcb11-/- mice. UDCA fed to abcb11-/- mice caused liver damage and the appearance of biliary tetra- and penta-hydroxy bile acids. Supplementation with UDCA in the absence of Bsep caused adverse effects in abcb11-/- mice.
authors.affiliation: British Columbia Cancer Research Centre, 675 W. 10 Ave., Vancouver, BC, Canada V5Z 1L3. vling@bccrc.ca.
authors.forename: Renxue
authors.initials: R
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Sheps
authors.forename: Dana
authors.initials: D
authors.lastname: Forrest
authors.forename: Alan F
authors.initials: AF
authors.lastname: Hofmann
authors.forename: Lee R
authors.initials: LR
authors.lastname: Hagey
authors.forename: Victor
authors.initials: V
authors.lastname: Ling
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001648:Bile Canaliculi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001692:Biological Transport; D002779:Cholestasis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004032:Diet; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D013655:Taurochenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C093491:ABCB11 protein, human; C489540:Abcc4 protein, mouse; C031655:ursodoxicoltaurine; C095122:multidrug resistance protein 3
keywords: ABC transporter; bile acid; bile salt export pump; progressive familial intrahepatic cholestasis