Most drugs that cause DILI do

Most drugs that cause DILI do further information so in an irregular and unpredicted fashion, also described as idiosyncratic events. Among those drugs withdrawn from the market due to severe liver injuries, hepatic failure typically occurred in fewer than 1 of 10 000 treated patients (Food and Drug Administration, 2009). Due to the low frequency, compounds causing severe DILI are challenging to identify in clinical trials and often remain unidentified until postmarketing monitoring when the drug has become available to a larger population (Bleibel et al., 2007). The initial mechanism of hepatotoxicity for drugs and their resulting metabolites varies, but independently of the origin of the first insult, the mitochondria seem to play a major role in the initiation and progression of DILI (Russmann et al.

, 2009; Xu et al., 2008). Initial cell stress can be caused by a wide range of mechanisms including glutathione depletion, binding to intracellular structures, and inhibition of hepatocellular functions, eg, canalicular bile salt secretion through inhibition of the bile salt export pump (BSEP/ABCB11) (Lee, 2003; Mackay, 1999; Pauli-Magnus and Meier, 2006; Rashid et al., 2004). BSEP mediates the ATP-dependent saturable efflux of monovalent bile salts across the canalicular membrane of the hepatocyte. The transporter constitutes the rate-limiting step in the transport of bile salts from the blood into the bile and thereby acts as an important determinant of bile flow (Gerloff et al., 1998). BSEP is almost exclusively expressed in the hepatocyte canalicular membrane, although low extrahepatic expression has been detected at the mRNA level (Hilgendorf et al.

, 2007; Langmann et al., 2003). The essential physiological function of BSEP in hepatobiliary bile salt secretion is apparent from several BSEP mutations resulting in absent or defective function of the protein. In progressive familial intrahepatic cholestasis type 2, the most severe form of BSEP deficiency syndrome, most of the afflicted patients have undetectable levels of BSEP protein at the canalicular membrane (Jansen et al., 1999; Strautnieks et al., 2008). This deficiency results in symptoms of cholestasis that develops before 6 months of age and progresses to end-stage liver disease within the first decade of life (Shneider, 2004; Whitington et al., 1994). Other mutations lead to milder forms of BSEP deficiency syndromes, GSK-3 such as benign recurrent intrahepatic cholestasis type 2.

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