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BSEP (bile salt export pump)

Aliases: ABC16, BRIC2, PFIC-2, PFIC2, PGY4, SPGP
Gene name: ATP binding cassette subfamily B, member 11 (ABCB11)



ABCB11, more commonly referred to as BSEP (Bile Salt Export Pump) is a uni-directional, ATP-dependent efflux transporter that plays an important role in the elimination of bile salts from the hepatocyte into the bile canaliculi for export into the gastrointestinal tract (GIT). It is almost exclusively expressed in the liver, with much lower levels reported in the kidney. It is predominantly of relevance to hepatotoxicity, as BSEP inhibition by a drug and/or its metabolites can result in the build-up of bile salts in the liver, which can lead to cholestasis and drug-induced liver injury (DILI). Compared to other drug transporters there are only few identified drug substrates and inhibitors of BSEP; thus, its involvement in drug-drug interactions (DDI) is very limited. The relevance of in vitro BSEP inhibition as a predictor of clinical outcomes is not clearly established, but whenever cholestatic liver injury is observed in clinical or preclinical trials, characterization of BSEP interactions should be considered. In contrast with the FDA guidance, the EMA guidance recommends consideration of in vitro BSEP inhibition testing for NCEs.


BSEP is predominantly expressed in the cholesterol-rich apical (canalicular) membrane of hepatocytes, where it functions in the secretion of bile salts from the liver into the bile canaliculi [1]. Low levels of mRNA expression have also been reported in the kidney, testis, and choroid plexus [2].
Function, physiology, and clinically significant polymorphisms
The BSEP transporter is a ~160 kDa protein with 12 putative membrane-spanning domains. BSEP mediates the hepatic excretion of monovalent conjugated bile acids. It shows high affinity for conjugated bile acids and a relatively poor affinity for unconjugated bile acids, in the order of: taurochenodeoxycholate ~ glychodeoxycholate > taurocholate ~ glycocholate [3]. BSEP also has a low affinity for a limited number of drugs that are substrates for MDR1 e.g. pravastatin [4], although a role for BSEP in clinical drug transport has not been established.
More than 300 SNPs of the ABCB11 gene have been reported, and half of these show possible associations with cholestatic disease, but only few have been investigated at the molecular level. Many ABCB11 polymorphisms are ethnicity-related [5, 6]. Mutations affecting the transmembrane helices tend to have severe functional consequences, suggesting a role of these motifs in substrate recognition, binding, and translocation. Possible outcomes of non-synonymous mutations include aberrant splicing, reduced plasma membrane expression, intracellular retention, and reduced or absent bile salt transport function. Low BSEP protein expression correlates with the C-allele at position 1457 in the ABCB11 gene [7]. In-vitro evaluations revealed 616A>G, 1674G>C, 1772A>G, and 3556G>A associated with significantly impaired taurocholate transport activity; the 890A>G variant had mildly impaired function and 3556G>A associated with reduced cell surface total protein expression compared with wild-type BSEP [5].  In addition to the severe Progressive Familial Intrahepatic Cholestasis type 2 (PFIC-2) and and a milder, transient disorder known as Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2), intrahepatic cholestasis of pregnancy (ICP) has also been linked to BSEP mutations [6].
BSEP expression is regulated by the farnesoid X receptor (FXR), and increased hepatic bile acids can induce transcription of Nrf2 [8].

Clinical significance

PFIC2 is characterized by severe jaundice, hepatomegaly, and high plasma levels of bile acids and aminotransferases. BRIC2 is associated with recurrent episodes of cholestasis and gallstone formation. Polymorphisms in BSEP transporter are associated with ICP and drug-induced cholestasis (reviewed in [9]). In particular, the polymorphism p.V444A increases susceptibility to both ICP and contraceptive-induced cholestasis, the latter condition probably being attributable to the inhibition of BSEP by oestrogen/progesterone metabolites [10].
Because humans, unlike rats, have no compensatory mechanism for the loss of this transporter. Due to this, mutations or chemical inhibitors can result in decreased biliary bile salt secretion, leading to decreased bile flow and accumulation of bile salts inside the hepatocyte, resulting in hepatotoxicity. Drugs such as bosentan, troglitazone and CI-1034 cause clinical hepatotoxicity that is related to inhibition of BSEP [11].
DILI is a rare but very serious clinical issue that in severe cases necessitates liver transplantation. Although there is a distinct association between modulation of BSEP function and DILI and/or cholestasis, the relationship is complex and multi-factorial. Nevertheless, the propensity of drugs to inhibit BSEP and thereby cause DILI can be predicted in vitro with remarkable accuracy. In a screen conducted with 85 pharmaceuticals, BSEP inhibition in vitro neatly correlated with cholestasis [12].  Such information may be helpful in the selection of candidates with reduced DILI liability [3] and/or the design of clinical strategies to manage/monitor DILI. For individualized patient management it may also be useful to consider that some polymorphisms of the ABCB11 gene, reviewed by Kubitz et al. [13], have been shown to increase proneness to DILI.

Regulatory requirements

Because of the association between BSEP and DILI, the EMA recommends that the potential for hepatically cleared new drugs and their metabolites be considered as inhibitors of BSEP.  The 2012 FDA guidance also recommends the consideration of BSEP inhibition studies when appropriate.  In case of a positive in vitro result, careful monitoring of hepatic function in clinical trials may be necessary.

Endogenous substrates
Substrates used experimentally
Substrate drugs
 Liver, Kidney (low)
bile acids, Taurocholic acid
bile acids such as taurochenodeoxycholate, taurocholate, taurodeoxycholate, glycocholate
Cyclosporine A, rifampicin, glibenclamide, glyburide



1.    Cheng, X., D. Buckley, and C.D. Klaassen, Regulation of hepatic bile acid transporters Ntcp and Bsep expression. Biochem Pharmacol, 2007. 74(11): p. 1665-76.
2.    Choudhuri, S., et al., Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab Dispos, 2003. 31(11): p. 1337-45.
3.    Kis, E., et al., BSEP inhibition - In vitro screens to assess cholestatic potential of drugs. Toxicol in Vitro, 2011.
4.    Kivisto, K.T. and M. Niemi, Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans. Pharm Res, 2007. 24(2): p. 239-47.
5.    Ho, R.H., et al., Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability. Pharmacogenet Genomics, 2010. 20(1): p. 45-57.
6.    Dixon, P.H., et al., Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut, 2009. 58(4): p. 537-44.
7.    Meier, Y., et al., Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology, 2006. 44(1): p. 62-74.
8.    Weerachayaphorn, J., et al., Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression. Hepatology, 2009. 50(5): p. 1588-96.
9.    Kosters, A. and S.J. Karpen, Bile acid transporters in health and disease. Xenobiotica, 2008. 38(7-8): p. 1043-71.
10.    Meier, Y., et al., Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump. World J Gastroenterol, 2008. 14(1): p. 38-45.
11.    Sahi, J., et al., Metabolism and transporter-mediated drug-drug interactions of the endothelin-A receptor antagonist CI-1034. Chem Biol Interact, 2006. 159(2): p. 156-68.
12.    Dawson, S., et al., In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. Drug Metab Dispos, 2012. 40(1): p. 130-8.
13.    Kubitz, R., et al., Genetic variations of bile salt transporters. Drug Discov Today Technol, 2014. 12: p. e55-67.












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