Key Event Title
Key Event Component
|transport||bile salt export pump||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Cholestatic Liver Injury induced by Inhibition of the Bile Salt Export Pump (ABCB11)||MolecularInitiatingEvent|
Level of Biological Organization
How This Key Event Works
The BSEP transporter protein is a prominent adenosine triphosphate-binding cassette transporter located at the canalicular pole of the hepatocyte membrane, which conveys bile acids from the hepatocyte cytosol into the bile canaliculi (Kis et al., 2012). BSEP can be directly cis-inhibited in a competitive way by several cholestasis-inducing drugs, including cyclosporine A, rifampicin, erythromycin estolate, 17α-ethinyl estradiol, bosentan, troglitazone and glibenclamide (Dawson et al., 2011; Kis et al., 2012; Morgan et al., 2010; Padda et al., 2011; Wagner et al., 2009; Zollner and Trauner, 2006 and 2008). As a result of BSEP inhibition, toxic bile acids, such as glycochenodeoxycholic acid, accumulate into the cytosol of the hepatocytes or bile canaliculi into so-called bile plugs (Kuntz and Kuntz, 2008).
How It Is Measured or Detected
A number of in vitro assays for measuring BSEP inhibition have been developed and successfully applied to demonstrate the cholestasis-inducing potential of drugs (Dawson et al., 2011; Kis et al., 2012; Morgan et al., 2010).
Evidence Supporting Taxonomic Applicability
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
Dawson, S., Stahl, S., Paul, N., Barber, J., Kenna, J.G. (2011). In vitro inhibition of the bile salt export pump correlates with risk of cholestatic drug-induced liver injury in humans. Drug Metab. Dispos. 40, 130-138.
Kis, E., Ioja, E., Rajnai, Z., Jani, M., Méhn, D., Herédi-Szabó, K., Krajcsi, P. (2012). BSEP inhibition: in vitro screens to assess cholestatic potential of drugs. Toxicol. In Vitro 26, 1294-1299.
Kuntz, E., Kuntz, H.D. (2008). Cholestasis. In Hepatology: Textbook and Atlas : History, Morphology, Biochemistry, Diagnostics, Clinic, Therapy 3rd edition (E. Kuntz E., H.-D. Kuntz Eds.), pp. 235-250. Springer, Heidelberg.
Morgan, R.E., Trauner, M., van Staden, C.J., Lee, P.H., Ramachandran, B., Eschenberg, M., Afshari, C.A., Qualls, C.W. Jr., Lightfoot-Dunn, R., Hamadeh, H.K. (2010). Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol. Sci. 118, 485-500.
Padda, M.S., Sanchez, M., Akhtar, A.J., Boyer, J.L. (2011). Drug-induced cholestasis. Hepatology 53, 1377-1387.
Wagner, M., Zollner, G., Trauner, M. (2009). New molecular insights into the mechanisms of cholestasis. J. Hepatol. 51, 565-580.
Zollner, G., Trauner, M. (2006). Molecular mechanisms of cholestasis. Wien. Med. Wochenschr. 156, 380-385.
Zollner, G., Trauner, M. (2008). Mechanisms of cholestasis. Clin. Liver Dis. 12, 1-26.