Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis

Abstract

The mouse mdr2 gene (and its human homologue MDR3, also called MDR2) encodes a P-glycoprotein that is present in high concentration in the bile canalicular membrane of hepatocytes. The 129/OlaHsd mice with a homozygous disruption of the mdr2 gene (-/- mice) lack this P-glycoprotein in the canalicular membrane. These mice are unable to secrete phospholipids into bile, showing an essential role for the mdr2 P-glycoprotein in the transport of phosphatidylcholine across the canalicular membrane. The complete absence of phospholipids from bile leads to a hepatic disease, which becomes manifest shortly after birth and shows progression to an end stage in the course of 3 months. The liver pathology is that of a nonsuppurative inflammatory cholangitis with portal inflammation and ductular proliferation, consistent with toxic injury of the biliary system from bile salts unaccompanied by phospholipids. Thus, the mdr2 (-/-) mice can serve as an animal model for studying mechanisms and potential interventions in nonsuppurative inflammatory cholangitis (in a generic sense) in human disease, be it congenital or acquired. When the mice are 4 to 6 months of age, preneoplastic lesions develop in the liver, progressing to metastatic liver cancer in the terminal phase. The mdr2 (-/-) mice therefore also provide a tumor progression model of value for the study of hepatic carcinogenesis. Interestingly, also in this regard, the model mimicks human disease, because chronic inflammation of the biliary system in humans may similarly carry increased cancer risk.