BSEP

Bile salt export pump (BSEP gene symbol ABCB11) mediates the biliary excretion of nonconjugated bile salts, such as taurocholic acid, glycocholic acid and cholic acid, and therefore is responsible for the formation of the bile acid-dependent bile flow [97, 98]. Its hereditary defect results in the acquisition of PFIC2, a potentially lethal disease which requires liver transplantation [17, 81, 82, 99]. As discussed in Section 12.5.2, the inhibition of BSEP following drug administration may result in cholestasis. 

More recently, a much more complex mechanism has been suggested for BSEP inhibition. By comparing the inhibitory effect of Mrp2 substrates on BSEP func-... 

Funk, C., Ponelle, C., Scheuermann, G., Pantze, M., Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat, Mol. Pharmacol. 2001, 59, 627-635. 

J., Kuliak-Ublick, G. A., Meier, P. J., Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver, Gastroenterology 2000, 118, 422-430. 

The phosphorescence of Pt2 (I OsKHq in aqueous solution is quenched by l,l-bis(2-sulfoethyl)-4,4f-bipyridinium inner salt (BSEP). Transient absorption attributable to BSEP ( nax 610 nn) is observed in flash kinetic spectroscopic studies of aqueous solutions containing Pt2( Os Hq and BSEP, thereby establishing an electron transfer quenching mechanism ... 

The luminescent excited state of MogClii reacts rapidly with electron acceptors(24). The powerfully oxidizing MogCli is produced in these reactions. Experiments with BSEP as acceptor in... 

ATP-dependent process, aided by the bile-salt excretion pump (BSEP) expression in the canalicular membrane. Conjugation increases the aqueous solubility of the bile adds, and renders these bile adds largely impermeable to the cell membranes of the intestine and duodenum hence, they are unable to leave the intestinal lumen. This allows bile-add levels to rise in the lumen, ultimately reaching sufficient concentrations to form micelles, which allow lipid emulsification and subsequent absorption. 

Transport of bile acids from blood into bile is rate limited by activity of the BSEP, and plays a crucial role both in control of intra-cellular concentrations... 

Figure 2.2 Secretion of bile acids and biliary components. Bile acids (BA) cross the hepatocyte bound to 3a-hydroxysteroid dehydrogenase and are exported into the canaliculus by the bile-salt export protein (BSEP). Phosphatidylcholine (PC) from the inner leaflet of the apical membrane is flipped to the outer layer and interacts with bile acids secreted by BSEP. BA, PC, together with cholesterol from the membrane form mixed micelles that are not toxic to epithelial membranes of the biliary tree. Aquaporins (AQP) secrete water into bile.

BSEP structure predicts multiple phosphorylation sites, including those for protein kinase C and A (PKC and PKA), within the predicted intra-cellular... 

In Vitro and In Vivo Assays to Measure BSEP Inhibition... 

---