MICE WITH HOMOZYGOUS DISRUPTION OF THE MDR2 P-GLYCOPROTEIN GENE - A NOVEL ANIMAL-MODEL FOR STUDIES OF NONSUPPURATIVE INFLAMMATORY CHOLANGITIS AND HEPATOCARCINOGENESIS

The mouse mdr2gene (and its human homologue MDR3, also called MDR2) en codes a P-glycoprotein that is present in high concentration in the bi le canalicular membrane of hepatocytes. The 129/OlaHsd mice with a hom ozygous disruption of the mdr2 gene (-/- mice) lack this P-glycoprotei n in the canalicular membrane. These mice are tenable to secrete phosp holipids into bile, showing an essential role for the mdr2 P-glycoprot ein in the transport of phosphatidylcholine across the canalicular mem brane. The complete absence of phospholipids from bile leads to a hepa tic disease, which becomes manifest shortly after birth and shows prog ression to an end stage in the course of 3 months. The liver pathology is that of a nonsuppurative inflammatory cholangitis with portal infl ammation and ductular proliferation, consistent with toxic injury of t he biliary system from bile salts unaccompanied by phospholipids. Thus , the mdr2 (-/-) mice can serve as an animal model for studying mechan isms and potential interventions in nonsuppurative inflammatory cholan gitis (in a generic sense) in human disease, be it congenital or acqui red. When the mice are 4 to 6 months of age, preneoplastic lesions dev elop in the liver, progressing to metastatic liver cancer in the termi nal phase. Tbe mdr2 (-/-) mice therefore also provide a tumor progress ion model of value for the study of hepatic carcinogenesis. Interestin gly, also in this regard, the model mimicks human disease, because chr onic inflammation of the biliary system in humans may similarly carry increased cancer risk.