Figure 1. Diagram illustrating the Ahr- and Nrf2-dependent signaling pathways and interactions between them.

Ahr is constitutively expressed in the cytoplasm of cells, and binds a variety of ligands including HAHs such as non-ortho PCBs. Upon ligand binding, Ahr translocates to the nucleus where it dimerizes with the Arnt and binds to XREs in the promoter region of numerous target genes including Phase I enzymes such as Cyp1a, some phase II enzymes, and the oxidant-responsive transcription factor Nrf2. Some planar structures that are potent Ahr agonists are poor substrates for metabolism by CYP1 enzymes (White et al. 1997) and can uncouple the CYP1 reaction cycle, generating ROS (Schlezinger et al. 2006). ROS from this and other sources can activate Nrf2. Nrf2 is found constitutively in the cytoplasm bound to a repressor protein, Keap1. Under unstressed conditions, Keap1 sequesters Nrf2 in the cytoplasm, targeting it for proteasomal degradation. ROS and electrophiles cause release and nuclear accumulation of Nrf2. In the nucleus, Nrf2, associates with small MAF proteins and binds to antioxidant response elements (AREs) in the promoter regions of a set of cytoprotective genes encoding antioxidant and phase II enzymes (Kobayashi et al. 2006). Among the Nrf2 target genes is Ahr, closing the loop on Ahr-Nrf2 cross-talk. See text for additional details.