Primary Sclerosing Cholangitis (PSC) is a complex puzzle. One of the important pieces of the PSC puzzle seems to be the regulation of pumps that affect the transport of bile and other compounds from the liver and intestine. This article reviews recent progress in characterizing these pumps (ABC transporters), and how they are affected by various medications.

Both Primary Sclerosing Cholangitis (PSC) and Primary Biliary Cirrhosis (PBC) are thought to be autoimmune cholestatic diseases that lead to inflammation and eventual destruction of the bile ducts of the liver, resulting in liver failure. Cholestasis is any condition in which bile excretion from the liver is blocked. This can occur either in the liver or in the bile ducts. PBC predominatly affects the small ducts, while PSC predominantly affects the large and medium-sized ducts. These diseases cause accumulation of toxic bile acids (such as deoxycholic acid (DCA)) in the liver, leading to cell death. The beneficial effects of ursodiol in PBC and PSC patients are in part attributable to a protective effect of this bile acid against toxic bile acids in liver cells (Paumgartner and Beuers, 2002). In addition, ursodiol increases bile transport activity, stimulating hepatobiliary secretion (Paoloni et al., 2002). Ursodiol (ursodeoxycholic acid; UDCA; URSO; Actigall) is a bile acid originally identified in black bears; the name ursodiol derives from the Latin name of the bear family, Ursidae (Hagey et al., 1993).

Anticholestatic effects of ursodiol have also been reported in other liver diseases, including progressive familial intrahepatic cholestasis, intrahepatic cholestasis of pregnancy, and liver disease associated with cystic fibrosis (Colombo et al., 1992; Angulo, 2002; Paumgartner and Beuers, 2002). The genetic bases of several of these diseases have been recently elucidated. Interestingly, a common theme of these diseases is impaired bile transport processes; specifically mutations in the genes encoding ABC transporters (Borst and Elferink, 2002; Elferink and Groen, 2003; Trauner and Boyer, 2003).

Bile formation is an osmotic process driven by the vectorial transport of actively transferred biliary components across the basolateral (sinusoidal) and apical (canalicular) hepatocyte membranes (Crocenzi et al., 2004). The latter appears to be the rate-limiting step of the overall blood-to-bile transfer. The ATP-binding cassette (ABC) superfamily of membrane transporters comprises novel ATP-dependent carriers that mediate canalicular transfer of several endogenous and exogenous substrates, and therefore play a key role in bile formation (Crocenzi et al., 2004).

"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. Mutations in the ABCB11 gene causing a functional disturbance in BSEP can result in familial intrahepatic cholestatis type II (Thompson and Strautnieks, 2001; Cavestro et al., 2002). Mice fed with the toxic bile acid, deoxycholic acid (DCA), show reduced expression of BSEP; ursodiol prevents this BSEP down-regulation caused by DCA and this may contribute to the protective effects of ursodiol in cholestatic liver disease (Paolini et al., 2002)

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. Diverse mutations in the ABCB4 gene cause functional disturbances of MDR3 and result in familial intraheptatic cholestatis type III, cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis (Dixon et al., 2000; Jacquemin, 2001; Lucena et al., 2003; Pauli-Magnus et al., 2004b; Rosmorduc et al., 2001; Rosmorduc et al., 2003; Strautnieks et al., 1998). Decreased transcription of the MDR3 gene is associated with primary hepatolithiasis (HL) in the Far East. This disease is characterized clinically by chronic proliferative cholangitis with frequent recurrences, but does not appear to be associated with mutations in the coding region of the ABCB4 gene (Kano et al., 2004).

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). It is noteable that fibrates induce Mdr2 expression in mice (Kok et al., 2003), and this may in part explain the beneficial effects of fibrates in primary sclerosing cholangitis (Kita et al., 2002) and primary biliary cirrhosis (Kurihara et al., 2000). In a very recent paper, Shoda et al. (2004) have suggested that the decreased function of ATP binding cassette protein B4 (ABCB4), which is rate-limiting for biliary phospholipid secretion, predisposes individuals to cholestasis and/or cholangitis. They show that bezafibrate may enhance the capacity of human hepatocytes to direct phospholipids into bile canaliculi via redistribution of ABCB4 to the canalicular membrane. This effect is mediated by the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa), for which bezafibrate is an activator. This provides a rationale for the use of bezafibrate to improve cholestasis and/or cholangitis that is due to impaired function of ABCB4 (Shoda et al., 2004).

Pauli-Magnus et al. (2004a) recently undertook a detailed analysis of the sequences of the ABCB4 (MDR3) and ABCB11 (BSEP) genes of healthy Caucasian individuals, and patients with PBC and PSC. No major differences between the groups were found. However, certain haplotypes of BSEP were associated with the severity of PBC (Pauli-Magnus et al., 2004a). Rosmorduc et al. (2004) also recently reported that variations in the ABCB4 (MDR3) gene do not contribute to PSC.

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. While Girordon et al. (2002) observed that the proportion of CFTR mutations is not significantly higher in PSC patients than in the general population, Sheth et al. (2003) observed that CFTR (ABCC7) mutations were found more frequently in PSC patients. Moreover, Blanco et al (2004) recently showed that when mice defective for CFTR (cftr-/-) are induced to have colitis, this results in bile duct injury resembling PSC in humans. While the contribution of CFTR mutations to PSC is still debatable, there seems to be growing evidence to support the idea that CFTR mutations are responsible for ideopathic pancreatitis (Choudari et al., 2004). The pancreas normally generates high concentrations of bicarbonate in the pancreatic fluid. CFTR interacts with a chloride/bicarbonate exchanger in pancreatic duct cells to achieve these high concentrations of bicarbonate. CFTR mutations that predominantly affect bicarbonate permeability lead to a predisposition to pancreatic dysfunction in humans (Whitcomb and Ermentrout, 2004).

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. Recently, 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). Evidence for linkage at chromosome 7q has been reported for both Crohn's disease and ulcerative colitis, and the gene for MDR1 (ABCB1) is located within this region. Polymorphism in the ABCB1 gene also seems to be an important factor in determining tacrolimus-induced neurotoxicity following liver transplantation (Yamauchi et al., 2002). Tacrolimus is a substrate of P-glycoprotein and this protein normally restricts the distribution of tacrolimus in the brain (Yamauchi et al., 2002). Similarly, Bonhomme-Faivre et al. (2004) have found that a polymorphisms in the MDR1 gene that influences intestinal P-glycoprotein expression is a major determinant of the optimal dose of Cyclosporine A in liver-transplant recipients.

Recently, Langmann et al. (2004) have reported that the expression of the MDR1 (ABCB1) gene is down-regulated in ulcerative colitis. This down-regulation of MDR1 (together with other defense genes) appears to be due to down-regulation of the transcription factor, pregnane X receptor (PXR), and may contribute to the pathophysiology of ulcerative colitis. PXR is a sensor of toxic bile acids that protects against liver toxicity (Staudinger et al., 2001). A drug that activates the pregnane X receptor (PXR) is rifampin (or rifampicin). This may in part explain the anticholestatic properties of rifampin, and why it is often beneficial in alleviating pruritus (itching) in PSC and PBC (Gillespie and Vickers, 1993).

Both MDR1 (ABCB1) and MRP2 (ABCC2) play important roles in the hepatobiliary system; both contribute to bile formation by transport of drugs, toxins, and waste products across the canalicular membrane. As they transport exogenous and endogenous substances, they reduce the body load of potentially harmful compounds (Dietrich et al., 2003). Mutations in the human multidrug resistance-associated protein 2 (MRP2) [also known as the Canicular Multispecific Organic Anion Transporter; CMOAT] encoded by the ABCC2 gene (gene map locus 10q24) lead to excessive accumulation of bilirubin, or hyperbilirubinemia II, also known as Dubin-Johnson syndrome (Materna and Lage, 2003; Shoda et al., 2003; Toh et al., 1999; Wada et al., 1998).

The breast cancer resistance protein, BRCP, encoded by the ABCG2 gene (gene map locus 4q22), is also expressed in the canalicular membrane of hepatocytes (Dietrich et al., 2003). This gene encodes a methotrexate polyglutamate transporter (Volk and Schneider, 2003) important in maintaining folate homeostasis (Ifergan et al, 2004). In mice, the breast cancer resistance protein (BCRP) (ABCG2) is necessary for protection against sensitivity to the dietary chlorophyll-breakdown product pheophorbide a (Jonker et al., 2002). Mice lacking this gene show severe, sometimes lethal phototoxic lesions on light-exposed skin. Pheophorbide a occurs in various plant-derived foods and food supplements (Jonker et al., 2002).

Phytosterolemia or sitosterolemia is a rare autosomal recessive disorder characterized by highly elevated plasma levels of plant sterols and cholesterol as a consequence of hyperabsorption and impaired biliary secretion of sterols. The disease is caused by mutations in two half-size ATP-binding cassette transporters, ABCG5 and ABCG8 (Heimer et al., 2002), both localized to gene map locus 2p21.

TAP1 (ABCB2) and TAP2 (ABCB3) are genes encoding ABC transporters involved in antigen presentation/processing (both genes are localized to the major histocompatibility locus: 6p21.3). Mutations in these transporters are implicated in several diseases, including: ankylosing spondylitis, insulin-dependent diabetes mellitus, rheumatoid arthritis, and celiac disease.

In total, defects in 14 different ABC transporter genes cause 13 different human diseases (Stefkova et al., 2004). The genes encoding ABC transporters are under tight control by nuclear receptors, which in turn respond to diet and stress (Stienstra et al., 2004). Because ABC transporters are extensively involved in hepatobiliary secretion and human diseases of the liver and bowel, the study of the genes encoding these transporters and their regulation remains a very active and productive area of research. This research field holds much promise for the development of new drugs to combat cholestatic diseases, and to understand why liver transplant patients differ in their responses to immunosuppressants.

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