[Frontiers in Bioscience 14, 4242-4256, January 1, 2009]

Liver diseases related to MDR3 (ABCB4) gene deficiency

Emmanuel Gonzales1,2, Anne Davit-Spraul3, Christiane Baussan3, Catherine Buffet4, Michele Maurice5, Emmanuel Jacquemin1,2

1Pediatric Hepatology and National Reference Centre for Biliary Atresia, Bicêtre Hospital, University of Paris - South 11, AP-HP, Paris, France, 2INSERM, UMR-S757, University of Paris - South 11, Orsay, France, 3Biochemistry, Bicetre Hospital, University of Paris - South 11, AP-HP, Paris, France, 4Hepatology, Bicetre Hospital, University of Paris - South 11, AP-HP, Paris, France, 5INSERM, U538, University Pierre and Marie Curie, Paris, France

TABLE OF CONTENTS

1. Abstract 2 .Introduction
3. The mdr2 knockout mouse : a model of liver pathology deficient in biliary phospholipid secretion
4. The spectrum of liver diseases related to MDR3 deficiency
4.1.Progressive familial intrahepatic cholestasis type 3 (PFIC3)
4.1.1. PFIC3 phenotype
4.1.2. Biliary lipids
4.1.3. Liver MDR3 immunostaining
4.1.4. MDR3 mutations
4.1.5. Genotype - phenotype correlation
4.1.6. Mechanism of liver pathology
4.2. Intrahepatic cholestasis of pregnancy
4.3. Cholesterol gallstone disease
4.4. Drug induced cholestasis
4.5. Transient neonatal cholestasis
4.6. Adult " idiopathic " biliary cirrhosis
5. Genotype - phenotype correlation among liver diseases related to MDR3 deficiency
6. Treatment of MDR3 deficiency (mainly PFIC3): present and future
7. References

1. ABSTRACT

Class III multidrug resistance P-glycoproteins, mdr2 in mice and MDR3 in human, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion.The role of a MDR3 (ABCB4) gene defect in liver disease has been initially proven in a subtype of progressive familial intrahepatic cholestasis called PFIC3, a severe pediatric liver disease that may require liver transplantation.Several MDR3 mutations have been identified in children with PFIC3 and are associated to low level of phospholipids in bile leading to high biliary cholesterol saturation index.MDR3 mutations are associated to loss of canalicular MDR3 protein and /or to loss of protein function.There is evidence that biallelic or monoallelic MDR3 defect causes or predisposes to 6 human liver diseases (PFIC3, adult biliary cirrhosis, low phospholipid associated cholelithiasis syndrome, transient neonatal cholestasis, intrahepatic cholestasis of pregnancy, drug induced cholestasis).Some patients with MDR3 deficiency may benefit from ursodeoxycholic acid therapy and could be good candidates to a targeted pharmacological approach and/or to cell therapy in the future.