Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene

Gastroenterology. 1996 Jul;111(1):165-71. doi: 10.1053/gast.1996.v111.pm8698195.


Background & aims: The mouse mdr2 gene encodes a P-glycoprotein expressed in the hepatocanalicular membrane. Inactivation of this gene causes lack of biliary phospholipid and cholesterol secretion and non-suppurative cholangitis. The aim of this study was to investigate the role of bile salt hydrophobicity in induction of liver pathology in mdr2 (-/-) mice.

Methods: Mice (+/+) wild type or (-/-) knockout for the mdr2 gene were fed with either purified control diet or this diet supplemented with cholate (0.1%) or ursodeoxycholate (0.5%) for 3, 6, or 22 weeks after weaning. Liver histology was semiquantitatively scored.

Results: Each mouse fed bile acid became the major constituent of the bile salt pool. The cholate diet during 22 weeks induced only very mild liver pathology in (+/+) mice. By contrast, lever histology had already deteriorated after 3 weeks in the (-/-) mice and caused pronounced inflammatory nonsuppurative cholangitis and fibrosis in the 75% of mice that survived. Dietary ursodeoxycholate had no effect on histology in (+/+) mice but improved liver pathology significantly in (-/-) mice compared with purified control diet; the decrease of ductular proliferation and portal inflammation was most prominent after 22 weeks.

Conclusions: The cholangiolitis and its sequelae in the mdr2 knockout mice depend on bile salt hydrophobicity.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / metabolism
  • Administration, Oral
  • Animals
  • Bile / metabolism
  • Chemical and Drug Induced Liver Injury
  • Cholangitis / chemically induced
  • Cholangitis / genetics
  • Cholangitis / metabolism
  • Cholic Acids / administration & dosage
  • Cholic Acids / adverse effects*
  • Cholic Acids / metabolism
  • Drug Resistance, Multiple / genetics
  • Food, Formulated
  • Gene Expression / drug effects*
  • Liver / pathology
  • Liver Cirrhosis, Biliary / chemically induced
  • Liver Cirrhosis, Biliary / genetics
  • Liver Cirrhosis, Biliary / metabolism
  • Liver Diseases / genetics
  • Liver Diseases / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Ursodeoxycholic Acid / administration & dosage
  • Ursodeoxycholic Acid / adverse effects*
  • Ursodeoxycholic Acid / metabolism


  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Cholic Acids
  • Ursodeoxycholic Acid
  • multidrug resistance protein 3