Figure 6
From: Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability
Working model for chlorpromazine-induced cholestatic toxicity.
Chlorpromazine induces oxidative stress23, which is associated with the disruption of the F-actin cytoskeleton integrity, leading to intracellular BA accumulation. The oxidative stress is further synergistically enhanced by chlorpromazine and the accumulated BAs at toxic concentrations. In addition, chlorpromazine inhibits the expression of ABCB11, encoding BSEP, further aggravating BA accumulation. The accumulated toxic BAs induce DR5 expression, leading to the activation of the death receptor signalling pathway. Collectively, these events result in cell death.
