The human bile salt export pump: characterization of substrate specificity and identification of inhibitors.
Article Details
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Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ
The human bile salt export pump: characterization of substrate specificity and identification of inhibitors.
Gastroenterology. 2002 Nov;123(5):1649-58.
- PubMed ID
- 12404239 [ View in PubMed]
- Abstract
BACKGROUND & AIMS: The bile salt export pump (BSEP) is the major bile salt transporter in the liver canalicular membrane. Our aim was to determine the affinity of the human BSEP for bile salts and identify inhibitors. METHODS: Human BSEP was expressed in insect cells. Adenosine triphosphatase (ATPase) assays were performed, and bile salt transport studies were undertaken. RESULTS: The BSEP gene, ABCB11, was cloned and a recombinant baculovirus was generated. Infected insect cells expressed a 140-kilodalton protein that was absent in uninfected and in mock-infected cells. An ATPase assay showed BSEP to have a high basal ATPase activity. Transport assays were used to determine the Michaelis constant for taurocholate as 4.25 micromol/L, with a maximum velocity of 200 pmol x min(-1) x mg(-1) protein. Inhibition constant values for other bile salts were 11 micromol/L for glycocholate, 7 micromol/L for glycochenodeoxycholate, and 28 micromol/L for taurochenodeoxycholate. Cyclosporin A, rifampicin, and glibenclamide were proved to be competitive inhibitors of BSEP taurocholate transport, with inhibition constant values of 9.5 micromol/L, 31 micromol/L, and 27.5 micromol/L, respectively. Progesterone and tamoxifen did not inhibit BSEP. CONCLUSIONS: The human BSEP is a high-affinity bile salt transporter. The relative affinities for the major bile salts differ from those seen in rodents and reflect the different bile salt pools. BSEP is competitively inhibited by therapeutic drugs. This is a potentially significant mechanism for drug-induced cholestasis.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Glyburide Bile salt export pump Protein Humans UnknownInhibitorDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Cyclosporine Bile salt export pump Protein Humans UnknownSubstrateInhibitorDetails Glyburide Bile salt export pump Protein Humans UnknownSubstrateInhibitorDetails Glycochenodeoxycholic Acid Bile salt export pump Protein Humans UnknownSubstrateInhibitorDetails Rifampicin Bile salt export pump Protein Humans UnknownInhibitorDetails Taurocholic acid Bile salt export pump Protein Humans UnknownSubstrateInducerDetails