The Bile Salt Export Pump

Department of Medicine, Institute of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland.
Pflügers Archiv - European Journal of Physiology (Impact Factor: 3.07). 03/2007; 453(5):611-20. DOI: 10.1007/s00424-006-0152-8
Source: PubMed

ABSTRACT Canalicular secretion of bile salts mediated by the bile salt export pump Bsep constitutes the major driving force for the generation of bile flow. Bsep is a member of the B-family of the super family of ATP-binding cassette transporters and is classified as ABCB11. Bsep has a narrow substrate specificity, which is largely restricted to bile salts. Bsep is extensively regulated at the transcriptional and posttranscriptional level, which directly modulates canalicular bile formation. Pathophysiological alterations of Bsep by either inherited mutations or acquired processes such as inhibition by drugs or disease-related down regulation may lead to a wide spectrum of mild to severe forms of liver disease. Furthermore, many genetic variants of Bsep are known, some of which potentially render individuals susceptible to acquired forms of liver disease.

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    • "Intra-hepatic cholestasis represents a frequent manifestation of DILI in humans (Lee, 2003). In many cases, it results from alterations of the hepatobiliary transporter system, in particular the bile salt export pump (BSEP), which is the most physiologically important canalicular bile transporter (Stieger et al., 2007). Other disturbances, such as altered cell polarity, disruption of cell-to-cell junctions and cytoskeleton disorganization, can also participate in cholestasis. "
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    ABSTRACT: Mechanisms involved in drug-induced cholestasis in humans remain poorly understood. Although cyclosporine A (CsA) and tacrolimus (FK506) share similar immunosuppressive properties, only CsA is known to cause dose-dependent cholestasis. Here, we have investigated the mechanisms implicated in early cholestatic effects of CsA using the differentiated human HepaRG cell line. Inhibition of efflux and uptake of taurocholate was evidenced as early as 15 minutes and 1 hour respectively after addition of 10 μM CsA; it peaked at around 2 hours and was reversible. These early effects were associated with generation of oxidative stress and deregulation of cPKC pathway. At higher CsA concentrations (≥50 μM) alterations of efflux and uptake activities were enhanced and became irreversible, pericanalicular F-actin microfilaments were disorganized and bile canaliculi were constricted. These changes were associated with induction of endoplasmic reticulum stress that preceded generation of oxidative stress. Concentration-dependent changes were observed on total bile acid disposition, which were characterized by an increase and a decrease in culture medium and cells respectively, after a 24-hour treatment with CsA. Accordingly, genes encoding hepatobiliary transporters and bile acid synthesis enzymes were differently deregulated depending on CsA concentration. By contrast, FK506 induced limited effects only at 25-50 μM and did not alter bile canaliculi. Our data demonstrate involvement of different concentration-dependent mechanisms in CsA-induced cholestasis and point out a critical role of endoplasmic reticulum stress in the occurrence of the major cholestatic features.
    Toxicological Sciences 06/2014; DOI:10.1093/toxsci/kfu122 · 4.48 Impact Factor
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    • "Bile acids are synthesized from cholesterol either by 7a-hydroxylation initiated by cholesterol 7a-hydroxylase or by 27-hydroxylation of cholesterol (Einarsson et al., 2000). Secretion of bile acids from the liver is mediated by the bile salt export pump (BSEP; Stieger et al., 2007). A negative feed-back and a positive feed-forward mechanism, respectively, synchronize and control the transcription of CYP7A1 and BSEP genes. "
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    ABSTRACT: Oleo gum resin secreted by Commiphora mukul, also known as gum guggul, has been used widely as an ayurvedic drug. Commiphora mukul is a short thorny shrub that is native to the Indian subcontinent. Oleo gum resin extracted by incision of the bark is a very complex mixture of gum, minerals, essential oils, terpenes, sterols, ferrulates, flavanones and sterones. Its active constituents, the Z- and E-guggulsterones, have been demonstrated to exhibit their biological activities by binding to nuclear receptors and modulating the expression of proteins involved in carcinogenic activities. Guggulsterones have also been reported to regulate gene expression by exhibiting control over other molecular targets including transcription factors such as nuclear factor (NF)-κB, signal transducer and activator of transcription (STAT) and steroid receptors. Considerable scientific evidence indicates the use of gum guggul as a therapeutic agent in the treatment of inflammation, nervous disorders, hyperlipidaemia and associated cardiac disorders such as hypertension and ischaemia, skin disorders, cancer and urinary disorders. This review highlights the taxonomic details, phytochemical properties and pharmacological profile of gum guggul. Copyright © 2012 John Wiley & Sons, Ltd.
    Phytotherapy Research 11/2012; 26(11):1594-605. DOI:10.1002/ptr.4647 · 2.40 Impact Factor
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    • "For example, although the name Sp-ABCB1b indicates similarity to human ABCB1/Pgp, the top NCBI Blastp hits were chicken ABCB1 (CMDR1) (e=0.0) and human ABCB11 (Bile salt export pump, BSEP) (e=0.0). BSEP transports bile salts across the canalicular plasma membrane (Stieger et al., 2007). Chicken Mdr1 is expressed in the thymus and bursa of embryos and may participate in lymphoid differentiation of T and B cells (Petrini et al., 1995). "
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    ABSTRACT: ATP-binding cassette (ABC) transporters are membrane proteins that regulate intracellular concentrations of myriad compounds and ions. There are >100 ABC transporter predictions in the Strongylocentrotus purpuratus genome, including 40 annotated ABCB, ABCC, and ABCG "multidrug efflux" transporters. Despite the importance of multidrug transporters for protection and signaling, their expression patterns have not been characterized in deuterostome embryos. Sea urchin embryos expressed 20 ABCB, ABCC, and ABCG transporter genes in the first 58 hr of development, from unfertilized egg to early prism. We quantified transcripts of ABCB1a, ABCB4a, ABCC1, ABCC5a, ABCC9a, and ABCG2b, and found that ABCB1a mRNA was 10-100 times more abundant than other transporter mRNAs. In situ hybridization showed ABCB1a was expressed ubiquitously in embryos, while ABCC5a was restricted to secondary mesenchyme cells and their precursors. Fluorescent protein fusions showed localization of ABCB1a on apical cell surfaces, and ABCC5a on basolateral surfaces. Embryos use many ABC transporters with predicted functions in cell signaling, lysosomal and mitochondrial homeostasis, potassium channel regulation, pigmentation, and xenobiotic efflux. Detailed characterization of ABCB1a and ABCC5a revealed that they have different temporal and spatial gene expression profiles and protein localization patterns that correlate to their predicted functions in protection and development, respectively.
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