3.A.1.201.2
Bile salt export pump, BSEP, ABCB11 or SPGP in the canalicular membrane of liver cells, is associated with progressive familial intrahepatic cholestasis-2 and benign recurrent intrahepatic cholestasis (Kagawa et al., 2008; Stindt et al. 2013; Park et al. 2016). It exports unconjugaged bile salts and glycine conjugates > taurine conjugates as well as the statin, pravastatin (Nigam 2015). BSEP mediates biliary excretion of bile acids from hepatocytes. Compounds based on GW4064 (Q96RI1), a representative farnesoid X receptor (RXR) agonist, enhance E297G BSEP transport activity (Misawa et al., 2012). Rescue of bile acid transport by ABCB11 variants by CFTR potentiators has been extensively documented as a possible treatment for progressive familial intrahepatic cholestasis-2 (Mareux et al. 2022).  BSEP is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. BSEP dysfunction, caused by mutations or induced by drugs is frequently associated with severe cholestatic liver disease. Liu et al. 2023 reported the cryo-EM structure of glibenclamide-bound human BSEP in nanodiscs, revealing the basis of small-molecule inhibition. Glibenclamide binds the apex of a central binding pocket between the transmembrane domains, preventing BSEP from undergoing conformational changes, and thus rationalizing the reduced uptake of bile salts. Two high-resolution structures of BSEP trapped in distinct nucleotide-bound states by using a catalytically inactivated BSEP variant (BSEP(E1244Q)) to visualize a pre-hydrolysis state, and wild-type BSEP trapped by vanadate to visualize a post-hydrolysis state. These studies provide structural and functional insight into the mechanism of bile salt extrusion and into small-molecule inhibition of BSEP, which may rationalize drug-induced liver toxicity (Liu et al. 2023). ABCB11 gene variations in children with progressive familial intrahepatic cholestasis type 2 have been identified (Riaz et al. 2024).  Estradiol 17β-d-glucuronide (E₂17G) induces cholestasis by triggering endocytosis and further intracellular retention of the canalicular transporters Bsep and Mrp2, in a cPKC- and PI3K-dependent manner, respectively. Pregnancy-induced cholestasis has been associated with an E₂17G cholestatic effect, and is routinely treated with ursodeoxycholic acid (UDCA). TUDC restores function and localization of Bsep/Mrp2 impaired by E₂17G, by preventing both cPKC and PI3K/Akt activation in a protein-phosphatase-independent manner (Medeot et al. 2024).  Cholesterol allosterically modulates the structure and dynamics of the taurocholate export pump (ABCB11) (Hosamani and Chakraborty 2024). Medicinal cannabis products inhibit ABCB11 (Anderson et al. 2022).  Patients with Primary Solerosing Colangitis (PSC) demonstrate altered expression levels and pattern of ABCB11 and ABCB4 which correlated with disease progression (Thoeni et al. 2019).  β-Sitosterol protects against  hepatotoxicity and cholestasis via FXR activation (Yan et al. 2025).