Effect of mdr2 mutation with combined tandem disruption of canalicular glycoprotein transporters by cyclosporine A on bile formation in mice.

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Elamiri A, Perwaiz S, Tuchweber B, Yousef IM

Effect of mdr2 mutation with combined tandem disruption of canalicular glycoprotein transporters by cyclosporine A on bile formation in mice.

Pharmacol Res. 2003 Nov;48(5):467-72. doi: 10.1016/s1043-6618(03)00187-7.

PubMed ID

12967592 [ View in PubMed

]

Abstract

UNLABELLED: The inhibition of canalicular glycoprotein transporters has been suggested as the cause of familial intrahepatic cholestasis. Mutations in multidrug resistance 3-glycoprotein (MDR3) gene induce progressive familial intrahepatic cholestasis type 3 (PFIC3). Phenotypically, mutation in mdr2 in mice resembles the disruption of MDR3 in human. Secondly, mutation in the bile salt exporting pump (BSEP)/sister of P-glycoprotein (spgp) gene causes progressive familial intrahepatic cholestasis type 2 in human. However, in spgp knock-out mice only a mild persistent cholestasis occurs. The aim of this study is to evaluate the effects of various P-glycoprotein (Pgp) transporters on bile formation and the canalicular transport of taurocholic acid (TCA) in an attempt to understand the combined role of these transporters in the pathogenesis of familial intrahepatic cholestasis. Total bile acid (TBA) and cholic acid secretion rate were decreased in the mdr2 knock-out mice. However, bile flow (BF) and the secretion of muricholic acids were increased. Secretion of cholesterol was negligible and no phospholipids were detected in bile of mdr2 knock-out mice. Treatment with cyclosporine A (CsA) decreased the BF, and the biliary secretion of bile salts (BS) and phospholipids as compared to wild type mice, but after the injection of TCA+CsA, the BF, and the biliary secretion of BS and lipids were increased as compared to the wild type mice treated with CsA alone. In the mdr2 knock-out mice, CsA treatment decreased the BF and the secretion of BS but after the injection of TCA+CsA, the BF and the biliary secretion of BS were increased and the phospholipid secretion was slightly stimulated as compared to the mdr2 knock-out mice treated with CsA alone. CONCLUSION: Disruption of the mdr2 gene and the inhibition of glycoprotein transporters by CsA induce cholestasis in mice which is characterized by reduced BF, BS and biliary lipid secretion. However, CsA treatment did not significantly increase the cholestatic effect in the mdr2 knock-out mice. The injection of TCA decreased the cholestatic effect in the mdr2 knock-out mice as well as the inhibition of glycoproteins transporters by CsA. These data suggest that mutation in the canalicular mdr2 is an important factor during the development of progressive familial cholestasis.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Cyclosporine	Canalicular multispecific organic anion transporter 1	Protein	Humans	Unknown	Inhibitor	Details