The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man

Abstract

The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man Paulusma, C.C.; Oude Elferink, R.P.J. Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Download date: 22 Mar 2019& p . 1 : Abstract The human Dubin-Johnson syndrome is an autosomal recessive liver disease characterized by a chronic conjugated hyperbilirubinemia. Patients have impaired hepatobiliary transport of many endogenous and xenobiotic compounds. A similar disease phenotype has been described for a naturally occurring mutant Wistar rat strain, the TR -rat, which is defective in the, functionally defined, canalicular multispecific organic anion transporter (cMOAT). The complementary DNA encoding this protein has been cloned from rat and recently from human liver. cMOAT is a new member of the ATPbinding cassette transporter family, and homologous to the multidrug resistance-associated protein 1. A mutation in the cMOAT gene is responsible for the phenotype observed in TR -rats. This information should soon lead to a complete genetic characterization of the human DubinJohnson syndrome.

Drug transporters in pharmacokinetics

“…Of those that have been identified, all are caused by loss of function of phase 4 carriers (Jansen 2001;Kubitz et al 2005). Examples are Dubin-Johnson syndrome caused by MRP2 (ABCC2) loss (Paulusma and Oude Elferink 1997) and subtypes of progressive familial intrahepatic cholestasis (PFIC), of which PFIC type 2 and PFIC type 3 are the most progressive cholestases caused by functional loss of BSEP (ABCB11) and of MDR3 (ABCB4; syn. Mdr2 in rodents), respectively (DeVree et al 1998;Maisonnette et al 2005;Wagner and Trauner 2005).…”

Iron beware: A common HFE gene polymorphism may prevent the accurate molecular diagnosis of homozygous hemochromatosis in low-risk, but not high-risk groups

“…3 Conjugated hyperbilirubinemia associated with Dubin-Johnson syndrome is a consequence of mutations in MRP1, a gene encoding a multidrug resistance protein also referred to as the canalicular multispecific organic anion transporter (cMOAT). 4 These associations between mutations in ABC transporters and characteristic liver diseases have yielded critical insights into molecular mechanisms of biliary lipid secretion.…”

Transport of Ethinylestradiol Glucuronide and Ethinylestradiol Sulfate by the Multidrug Resistance Proteins MRP1, MRP2, and MRP3

“…MRP1 (ABCC1) is localized in the basolateral membranes of polarized cells (Evers et al, 1996;Cole and Deeley, 1998) and is expressed in all tissues except the liver (Zaman et al, 1994). In contrast, MRP2 (ABCC2) is expressed in the canalicular membrane of hepatocytes, the apical membrane of the small intestine, the apical membrane of the proximal tubules of the kidney, and placental trophoblasts (Paulusma and Oude Elferink, 1997;Schaub et al, 1997Schaub et al, , 1999St-Pierre et al, 2000). MRP2 therefore may be involved in hepatobiliary-, renal-, and intestinal excretion of compounds, and protection of the fetus.…”