BSEP inhibition: in vitro screens to assess cholestatic potential of drugs.

Abstract

Bile salt export pump (BSEP, ABC11) is a membrane protein that is localized in the cholesterol-rich canalicular membrane of hepatocytes. Its function is to eliminate unconjugated and conjugated bile acids/salts from hepatocyte into the bile. In humans there is no compensatory mechanism for the loss of this transporter. Mutations of BSEP result in a genetic disease, called progressive familial intrahepatic cholestasis type 2 (PFIC2), that is characterized with decreased biliary bile salt secretion, leading to decreased bile flow and accumulation of bile salts inside the hepatocyte, inflicting damage. BSEP inhibitor drugs produce similar bile salt retention that may lead to severe cholestasis and liver damage. Drug-induced liver injury is a relevant clinical issue, in severe cases ending in liver transplantation. Therefore, measurement of BSEP inhibition by candidate drugs has high importance in drug discovery and development. Although several methods are suitable to detect BSEP-drug interactions, due to interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation, they have limitations. This review summarizes appropriate in vitro methods that could be able to predict BSEP-drug candidate interactions in humans before the start of clinical phases.

• Authors: Emese Kis, Enikő Ioja, Zsuzsa Rajnai, Márton Jani, Dóra Méhn, Krisztina Herédi-Szabó, Peter Krajcsi
• Journal: Toxicology in vitro : an international journal published in association with BIBRA (Toxicol In Vitro) Vol. 26 Issue 8 Pg. 1294-9 (Dec 2012) ISSN: 1879-3177 [Electronic] England
• PMID: 22120137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• ABCB11 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters
• Bile Acids and Salts

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics)
• Animals
• Bile Acids and Salts (metabolism)
• Chemical and Drug Induced Liver Injury (etiology, physiopathology)
• Cholestasis (chemically induced, physiopathology)
• Cholestasis, Intrahepatic (genetics, physiopathology)
• Drug Design
• Humans
• Severity of Illness Index
• Species Specificity