Background: Drug-induced Liver Injury (DILI) has received increasing attention over the past decades, as
it represents the leading cause of drug failure and attrition. One of the most prevalent and severe forms of DILI involves
the toxic accumulation of bile acids in the liver, known as Drug-induced Cholestasis (DIC). Traditionally,
DIC is studied by exploring the inhibition of hepatic transporters such as Bile Salt Export Pump (BSEP) and
multidrug resistance-associated proteins, predominantly through vesicular transport assays. Although this approach
has identified numerous drugs that alter bile flow, many DIC drugs do not demonstrate prototypical transporter inhibition,
but rather are associated with alternative mechanisms.
Methods: We undertook a focused literature search on DIC and biliary transporters and analyzed peer-reviewed
publications over the past two decades or so.
Results: We have summarized the current perception regarding DIC, biliary transporters, and transcriptional regulation
of bile acid homeostasis. A growing body of literature aimed to identify alternative mechanisms in the development
of DIC has been evaluated. This review also highlights current in vitro approaches used for prediction of DIC.
Conclusion: Efforts have continued to focus on BSEP, as it is the primary route for hepatic biliary clearance. In
addition to inhibition, drug-induced BSEP repression or the combination of these two has emerged as important
alternative mechanisms leading to DIC. Furthermore, there has been an evolution in the approaches to studying DIC
including 3D cell cultures and computational modeling.