Drug-induced liver injury is an important clinical entity, which can be grouped into cholestatic liver injury, hepatocellular liver injury, and mixed liver injury. Cholestatic liver injury is characterized by a reduction in bile flow and the retention within hepatocytes of cholephilic compounds such as bile salts that cause hepatotoxicity.
Bile salts are taken up by hepatocytes in a largely sodium-dependent manner and to a lesser extent in a sodium-independent manner. The former process is mediated by NTCP (sodium/bile acid cotransporter) and the latter by OATPs (organic anion transporting polypeptides). OATPs have broad substrate specificity and mediate the uptake of many drugs into hepatocytes. Bile salts are exported from hepatocytes into the biliary tree by BSEP (bile salt export pump). Inhibition of BSEP by drugs or drug metabolites leads to drug-induced cholestasis. BSEP can be inhibited directly from within the hepatocyte or indirectly by a mechanism that first requires canalicular secretion of the perpetrator. In cholestatic liver disease, expression of hepatocellular uptake transporters is generally reduced, while the expression of the canalicular export systems tends to be preserved. This adaptation is controlled by nuclear receptors and transcription factors. Genetic variants of BSEP may be risk factors for drug-induced cholestasis. So far, studies have associated the c.1331 T variant of the ABCB11 gene, encoding a p.V444A substitution in BSEP, as a potential risk factor. Additional risk factors may be genetic variants of uptake transporters or other export transporters for drugs or their metabolites.