ABC transporter, Primary Sclerosing Cholangitis Literature

Primary Sclerosing Cholangitis Literature

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Scientific Literature, ABC transporter

"ABC" stands for "Adenosine triphosphate-Binding Cassette". Adenosine triphosphate (ATP) is a high-energy compound involved in many aspects of cellular metabolism; it is essentially the energy currency of living cells. ABC transporters are membrane proteins that bind and consume ATP to provide the energy to move molecules across cell membranes (Borst and Elferink, 2002). Molecules transported by these proteins include cholesterol, bile acids and various drugs.

There are a total of 48 ABC transporter genes identified in the human genome, and these can be broadly divided into 7 distinct subfamilies; subfamilies A, B, C, D, E, F and G (Dean et al., 2001). Within each subfamily there can be numerous different forms. For example, gene ABCB11, represents the eleventh member of the B subfamily of ABC transporters, while ABCC7 represents the seventh member of the C subfamily. Each gene is localized to a different chromosome region, and represents the template for a distinct protein with distinct preferences for the types of molecules that it transports. Each gene may exhibit a distinct expression pattern in specific membranes of specific cells and specific organs. These expression patterns are influenced by a number of nuclear receptor transcription factors, and may be affected by certain drugs or disease states.

The bile-salt export pump (BSEP) [also known as Sister of P-glycoprotein (SPGR)] is encoded by the ABCB11 gene (gene map locus 2q24), and is the main pump that mediates the cellular excretion of numerous conjugated bile salts (Lang et al., 2006) [see BSEP and OMIM: 603201 for further details]. Various forms of intrahepatic cholestasis are associated with mutations/polymorphisms in the ABCB11 (BSEP) gene. Mutations in ABCB11 can also cause early clinical manifestations and progression to hepatocellular failure in childhood (Hierro and Jara, 2005). Mutations in the ABCB11 are associated with familial intrahepatic cholestasis type 1 (Nobili et al., 2006).

The class III multi-drug resistance P-glycoprotein 3 (MDR3) [also known as PGY3 or Multidrug Resistance 3] is encoded by the ABCB4 gene (gene map locus 7q21.1), and is thought to be an ATP-dependent "flippase" that moves phospholipids from the inner to the outer leaflet of the canalicular membrane. The mouse equivalent of the human MDR3 protein is Mdr2, encoded by the gene Abcb4. Mice deficient in Mdr2 (mdr2(-/-)) develop sclerosing cholangitis by a multistep process involving regurgitation of bile from leaky ducts into the portal tracts. This leads to induction of periductal inflammation, followed by activation of periductal fibrogenesis, finally causing obliterative cholangitis owing to atrophy and death of bile duct epithelial cells (Fickert et al., 2004) [see MDR or MRP and OMIM: 171060 for further details]. The ABCB4 (MDR3) gene is disrupted in forms of progressive familial intrahepatic cholestasis (PFIC) and related disorders. Degiorgio et al. (2007) have characterized 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3). Mutations in this gene may also be associated with intrahepatic cholestasis of pregnancy (Dixon et al., 2000; Floreani et al., 2007). Trauner et al. (2007) consider MDR3 (ABCB4) gene defects as a paradigm for the genetics of adult cholestatic syndromes: "MDR3 variants could play a role as modifier gene in primary biliary cirrhosis and primary sclerosing cholangitis, but their exact role needs further clarification." Karlsen et al. (2007) have shown that variation in the MDR3 gene influences disease progression in PSC patients and disease susceptibility in epistatic interaction with a polymorphism in the organic solute transporter-alpha (OST-alpha) gene.

Cystic fibrosis has long been known to be caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an "ABC" chloride transporter, encoded by the ABCC7 gene (gene map locus 7q31.2). Interestingly, this gene is highly expressed in bile duct epithelial cells (Cohn et al., 1993), and the bile duct lesions seen in liver disease associated with cystic fibrosis show striking similarity to that seen in PSC. Sheth et al. (2003) observed that CFTR (ABCC7) mutations were found more frequently in PSC patients. Moreover, Blanco et al. (2004) have shown that when mice defective for CFTR (cftr-/-) are induced to have colitis, this results in bile duct injury resembling PSC in humans [see cystic fibrosis or CFTR and OMIM: 602421 for further details].

The human multidrug resistance 1 P-glycoprotein, MDR1, encoded by the gene ABCB1 (gene map locus 7q21.1), is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics. P-glycoprotein is an ATP-dependent efflux pump that contributes to the protection of the body from environmental toxins (Schwab et al., 2003a). It transports a huge variety of structurally diverse compounds. P-glycoprotein is involved in limiting absorption of xenobiotics from the gut lumen, and in biliary and urinary excretion of its substrates. P-glycoprotein can be inhibited or induced by xenobiotics, thereby contributing to variable drug disposition and drug interactions. Several polymorphisms have been identified in the MDR1 (ABCB1) gene, some of which can affect P-glycoprotein expression and function (Schwab et al., 2003a). Certain of the mutations appear to influence susceptibility to inflammatory bowel disease, including ulcerative colitis (Brant et al., 2003; Schwab et al., 2003b) [see MDR or MRP and OMIM: 171050 for further details].

Number of references = 1062


David and Judy Rhodes Last Update: 3/6/2010