Bile salt export pump: Drug-induced liver injury and assessment approaches

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Bile acid homeostasis is maintained through the tightly regulated enterohepatic circulation of bile acids. Biliary excretion of bile acids by bile salt export pump (BSEP) is the rate-limiting step in the circulation. Impairment of BSEP function and expression results in excessive accumulation of hepatic bile acids, which are toxic to hepatocytes. Indeed, genetic deficiencies in BSEP resulting in diminished or reduced BSEP activity or cell surface expression directly cause cholestatic liver diseases including progressive familial intrahepatic cholestasis type II (PFICII) and benign intrahepatic cholestasis (BRIC) or predispose to intrahepatic cholestasis of pregnancy and drug-induced cholestasis. Drugs or compounds inhibiting BSEP activity, repressing BSEP transcription, or reducing cell surface expression of BSEP protein have the potential to induce cholestatic liver injury. Accumulating evidences reveal that inhibition of BSEP activity is one of the mechanisms for drug-induced liver injury (DILI). Studies also show that repression of BSEP transcription or reduction of its canalicular membrane expression contribute to a spectrum of cholestatic injuries. Currently, a number of in vitro methods are employed to assess the cholestatic potentials of drugs or compounds. These methods can be divided into three categories based on the mechanisms of action of the test drugs or compounds: (1) inhibition of BSEP activity; (2) repression of BSEP transcription; and (3) reduction of cell surface expression of BSEP protein. Here, applications, advantages, and limitations of these in vitro approaches are described and discussed.

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Methods in Pharmacology and Toxicology