Disease relevance of ABCB11

• It is now recognized that mutations in the gene encoding this protein (ABCB11) are responsible for a subgroup of infants and children with progressive familial cholestasis (PFIC-2), a cholestatic disorder causing extreme pruritus, growth failure, and progression to cirrhosis in the first decade of life [1].
• Finally, dysfunction of individual bile salt transporters such as BSEP, on account of genetic mutations, steric inhibition, suppression of gene expression, or disturbed signaling, is an important cause of cholestatic liver disease [2].
• BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis [3].
• BSEP is a vulnerable target for inhibition by estrogen metabolites, drugs such as cyclosporine A, and abnormal bile salt metabolites, all of which can cause retention of bile salts and consequently intrahepatic cholestasis [4].
• In humans, mutations in the BSEP gene are associated with a very low level of bile acid secretion and severe cholestasis [5].
• Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)] [6].

Psychiatry related information on ABCB11

• BACKGROUND: We determined whether genetic variability in the gene encoding the bile salt export pump (BSEP) contributes to individual differences in susceptibility to the development of intrahepatic cholestasis of pregnancy (ICP) [7].
• When withdrawing parenteral antibiotics from a non-decisional dementia patient with sepsis at the request of his legal guardian, M3 and 4 expressed a greater concern for violating medical practice standards while PGY4 and 5 showed a greater concern for the violation of personal religious or ethical beliefs [8].

High impact information on ABCB11

• A subgroup characterized by normal serum cholesterol and gamma-glutamyltranspeptidase (gammaGT) levels is genetically heterogeneous with loci on chromosomes 2q (PFIC2) and 18q [9].
• The phenotype of the PFIC2-linked group is consistent with defective bile acid transport at the hepatocyte canalicular membrane [9].
• Five mutations, G238V, E297G, G982R, R1153C, and R1268Q, prevented the protein from trafficking to the apical membrane, and E297G, G982R, R1153C, and R1268Q also abolished taurocholate transport activity, possibly by causing Bsep to misfold [10].
• The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II [10].
• To evaluate these mechanisms, we introduced seven PFIC II-associated missense mutations into rat Bsep and assessed their effects on Bsep membrane localization and transport function in MDCK and Sf9 cells, respectively [10].

Chemical compound and disease context of ABCB11

• In contrast to CDCA and GW4064, lithocholate (LCA), a hydrophobic bile acid and a potent inducer of cholestasis, strongly decreased BSEP expression [11].
• FXR also targets sodium taurocholate cotransport peptide and bile salt export pump (protein) genes to limit bile salt uptake and enhance export, respectively, which prevents bile salt toxicity [12].
• Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy [13].
• Other events such as apoptosis and PPARgamma-dependent steatosis could be also mediated by TGZ, while inhibition of bile salt export pump, a cause of TGZ-induced cholestasis, may be caused by the TGZ sulfate [14].

Biological context of ABCB11

• An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type [15].
• All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin [15].
• The authors have recently developed in vitro high-speed screening and quantitative structure-activity relationship analysis methods to investigate the interaction of ABCB11 with a variety of compounds [16].
• Whereas the downregulation of the unidirectional sinusoidal uptake system NTCP protects the hepatocyte from further intracellular accumulation of bile salts, the relative preservation of canalicular BSEP expression serves to uphold bile salt secretion, even in complete biliary obstruction [17].
• Our data further support an involvement of MDR3 genetic variation in the pathogenesis of ICP, whereas analysis of BSEP sequence variation indicates that this gene is probably less important for the development of pregnancy-associated cholestasis [18].

Anatomical context of ABCB11

• Under physiological conditions, the sinusoidal ABCC4 may compete with canalicular ABCB11 for bile acids and thereby play a key role in determining the hepatocyte concentration of bile acids [19].
• After diffusion (bound by intracellular bile salt-binding proteins) to the canalicular membrane, monoanionic bile salts are secreted into bile canaliculi by the bile salt export pump Bsep (rodents) or BSEP (humans) [20].
• Inhibition of bile acid transport across Na+/taurocholate cotransporting polypeptide (SLC10A1) and bile salt export pump (ABCB 11)-coexpressing LLC-PK1 cells by cholestasis-inducing drugs [21].
• Mutational analysis of ABCB11 was performed in leukocyte DNA from available patients and parents [22].
• Spgp is a Mr approximately 170,000 glycosylated plasma membrane protein localized to the canalicular surface of hepatocytes in the rat liver [23].

Associations of ABCB11 with chemical compounds

• Significant ATP-dependent uptake of pravastatin by human BSEP (hBSEP)- and rat BSEP (rBsep)-expressing membrane vesicles was observed, and the ratio of the uptake activity of pravastatin to that of taurocholic acid (TCA) by hBSEP was 3.3-fold higher than that by rBsep [24].
• The K(m) value of pravastatin for hBSEP was 124 muM [24].
• A mutual inhibition study between TCA and pravastatin revealed that they competitively interact with hBSEP [24].
• Several statins inhibited the hBSEP- and rBsep-mediated uptake of TCA; however, the specific uptake of other statins (cerivastatin, fluvastatin, and pitavastatin) by hBSEP and rBSEP was not detected [24].
• The well known cholestatic drugs, rifampicin, rifamycin SV, glibenclamide, and cyclosporin A, reduced the basal-to-apical transport and the apical efflux clearance of taurocholate across NTCP- and BSEP-coexpressing cell monolayers [21].

Physical interactions of ABCB11

• The sister gene of P-glycoprotein (Spgp) is a liver-specific ATP-binding cassette protein highly related to the P-glycoprotein (Pgp) family (S. Childs et al, Cancer Res., 55: 2029-2034, 1995) [23].

Regulatory relationships of ABCB11

• Reducing endogenous FXR levels using RNA interference fully repressed the bile salt-induced ABCB11 expression [25].
• Guggulsterone antagonizes farnesoid X receptor induction of bile salt export pump but activates pregnane X receptor to inhibit cholesterol 7alpha-hydroxylase gene [26].

Other interactions of ABCB11

• In conclusion, PFIC-2 may be reliably diagnosed by immunofluorescence, whereas the diagnosis of PFIC-3 requires gene-sequencing [27].
• In contrast, MRP2 and BSEP mRNA levels were not affected under these conditions [28].
• Because fluorescent substrates allow the development of a high-throughput screening method, we examined the transport by NTCP and BSEP of fluorescent bile acids as well as taurocholate [21].
• Bile acid transporters, i.e., bile salt export pump and Na(+)-taurocholate cotransporting polypeptide, and the sinusoidal transporter, OAT2, were down-regulated by all the tested chemicals [29].
• It has been reported that bosentan, an endothelin receptor antagonist, inhibits Bsep, which may lead to cholestatic liver injury due to the intracellular accumulation of bile salts, while increasing bile salt-independent bile flow [30].

Analytical, diagnostic and therapeutic context of ABCB11

• Therefore, 149 healthy Caucasian control individuals (control group) were compared to 76 PBC and 46 PSC patients with respect to genetic variations in BSEP and MDR3 [3].
• Although mRNA of BSEP was detectable and its expression confirmed by Western blotting, its very low expression (higher in hTr than in whole placenta and hCC) did not permit its detection by immunohistochemistry [31].
• METHODS: Liver tissue specimens were taken from 20 patients with cholesterol calculus and from 10 patients with normal liver. mRNA and protein expressions of BSEP, MRP2, and MDR3 were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively [32].
• Introduction of E297G and D482G mutations into the human BSEP gene by site-directed mutagenesis resulted in a significant reduction in the BSEP expression level, which was associated with impaired membrane trafficking [33].
• Tissue distribution assessed by Northern blotting revealed predominant, if not exclusive, expression of spgp in the liver, where it was further localized to the canalicular microvilli and to subcanalicular vesicles of the hepatocytes by in situ immunofluorescence and immunogold labeling studies [34].

References