Mechanisms of Drug-Induced Cholestasis.

Cholestasis can be defined as any situation of impaired bile secretion with concomitant accumulation of bile acids in the liver or in the systemic circulation. A variety of factors may evoke cholestasis, including genetic disorders, metabolic pathologies, infectious diseases, immunogenic stimuli, and drugs. Drug-induced cholestasis is a mechanistically complex process. At least three triggering factors of drug-induced cholestasis have been described, including effects on drug transporters, various hepatocellular changes, and altered bile canaliculi dynamics. These stimuli induce two cellular responses, each typified by a number of key events, namely a deteriorative response activated by bile acid accumulation and an adaptive response aimed at decreasing the uptake and increasing the export of bile acids into and from the liver, respectively. The mechanistic scenario of drug-induced cholestasis is described in this chapter.