Fig. 8.

Model of metformin-mediated CAR phosphorylation and deactivation. The schematic figure illustrates that metformin inhibits both the nuclear translocation and nuclear activation of CAR, and represses CYP2B6 expression induced by PB and CITCO. In the cytoplasm, metformin enhances CAR phosphorylation thereby blocks its nuclear translocation, primarily through the AMPK and ERK1/2 pathways, with the p38 MAPK and EGFR signaling negligibly involved. Inside the nucleus, metformin can disrupt the interaction between CAR and coactivators, which was enhanced by the direct hCAR activator CITCO. The solid and dashed lines indicate strong and weak interactions, respectively. The arrows show activation and the blunt-head lines demonstrate inhibition.