THE ROLE OF BILE-SALT COMPOSITION IN LIVER PATHOLOGY OF MDR2 (- -) MICE - DIFFERENCES BETWEEN MALES AND FEMALES/

Background/Aims: The mouse mdr2 gene encodes a P-glycoprotein expresse d in the canalicular membrane of the hepatocyte. Mice in which this ge ne has been inactivated (mdr2 -/-) show a defect in biliary phospholip id and cholesterol secretion and develop non-suppurative cholangitis. We hypothesized that secretion of bile salts without lipids initiates this liver disease. Methods: To delineate the pathologic process, mdr2 (-/-) mice were fed different bile salt-supplemented diets for 22 wee ks after weaning. Aspects of liver pathology including eosinophilic bo dies, portal inflammation, ductular proliferation, mitotic activity an d fibrosis were semi-quantitatively scored. Results: It was observed t hat liver pathology was more severe in female than in male mice when f ed a purified control diet. This correlated with a more hydrophobic bi le salt composition of female vs. male bile. When increasing amounts o f cholate were added to the diet (0.01% and 0.1%), the secretion of ta urocholate increased and this was accompanied by a more severe liver p athology. At the high dose of cholate (0.1%), the bile salt compositio ns of male and female mice became similar, as did the severity of the histological score. Addition of cholate to the diet did not induce liv er pathology in (+/+) mice. Addition of ursodeoxycholate to the diet ( 0.5%) led to a near complete replacement of biliary bile salts by taur oursodeoxycholate and this reduced pathology and dissipated the differ ence between males and females. Conclusions: These observations suppor t our hypothesis that liver pathology in the mdr2 (-/-) mouse is cause d by bile salts and depends on the hydrophobicity c.q. cytotoxicity of biliary bile salts.