title: Identification of a novel 974C-->G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids.
abstract: Rifampicin (RIF) and ursodeoxycholic acid (UDCA) therapies have beneficial effects in chronic cholestatic diseases. These may result in part from the induction of multidrug-resistance protein 2 (MRP2/ABCC2) expression in the liver and kidney. However, the precise mechanisms by which RIF and UDCA act in cholestasis remain unclear. In the present study, we report the effects of chronic administration of both drugs in a patient with Dubin-Johnson syndrome (DJS), an inherited autosomal recessive disorder characterized by the absence of functional MRP2 protein at the canalicular hepatocyte membrane. A novel 974C-->G nonsense mutation was identified in the MRP2 gene sequence from this patient. RIF induced further increase in conjugated bilirubinemia, whereas concomitant administration of RIF and UDCA led to a dramatic rise in serum bile acid concentrations. These biochemical effects, which are in marked contrast to those observed in cholestatic settings, were concomitant with an increased MRP3, but not MRP4, expression on basolateral hepatocyte membrane. Such findings highlight the key role of MRP2 in the pharmacological properties of RIF and UDCA and suggest that both drugs should be used with caution in pathologic settings in which MRP2 expression may be downregulated, as in advanced stage of cholestatic diseases.
authors.affiliation: Service d'Hépatologie, Centre National deRéférence des Maladies Inflammatoires du Foie et des Voies Biliaires, Hôpital Saint-Antoine, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Corpechot
authors.forename: Chen
authors.initials: C
authors.lastname: Ping
authors.forename: Dominique
authors.initials: D
authors.lastname: Wendum
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Véronique
authors.initials: V
authors.lastname: Barbu
authors.forename: Raoul
authors.initials: R
authors.lastname: Poupon
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002756:Cholagogues and Choleretics / Q000008:administration & dosage; D018389:Codon, Nonsense / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006801:Humans; D007566:Jaundice, Chronic Idiopathic / Q000097:blood / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D012293:Rifampin / Q000008:administration & dosage; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage
chemical_list: D001647:Bile Acids and Salts; D001663:Bilirubin; D002756:Cholagogues and Choleretics; D018389:Codon, Nonsense; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012293:Rifampin; D014580:Ursodeoxycholic Acid; C000715087:ABCC2 protein, human