Aryl Hydrocarbon Receptor (AHR. The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that regulates the transcription of the CYP1A and CYP1B subfamilies as well as other target genes. A member of the basic helix-loop-helix PER-ARNT-SIM transcription factory family (Yi-Zhong, Hogenesch, & Xxxxxxxxx, 2000), AHR is primarily involved in mediating the response to environmental toxins such as 2,3,7,8- Tetrachlorodibenzo-p-dioxin (TCDD) or the carcinogenic polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke (Li & Wang, 2010) (Xxxx & Xxxxxxxx-Xxxxxxxx, 2010). Besides its role in toxicology, the AHR is also known to play other important roles in development and the immune system. For example, AHR regulates Th17 cell differentiation (Kimura, Naka, Nohara, Fujii-Kuriyama, & Kishimoto, 2008); while studies with AHR knockout mice show that the AHR is involved in both neuronal development (Gohlke, Stockton, Sieber, Foley, & Xxxxxxx, 2009) and cardiovascular function (Zhang, 2011). In its inactive state, the AHR is sequestered primarily in the cytoplasm, bound in a complex with heat shock protein (Hsp90), X-associated protein 2 (XAP2), and p23 (Xxxxxxxx & Xxxxxx, 2002). Upon ligand binding, the AHR undergoes a conformational change and exposes a nuclear localization signal (Ikuta, Eguchi, Tachibana, Yoneda, & Kawajiri, 1998). The activated AHR then dissociates from this cytoplasmic complex and translocates to the nucleus where it dimerizes with its partner, AHR nuclear translocator (ARNT) (Xxxxx, Xxxxx-Xxxxxxxx, & Xxxxxxxxx, 1992). In the nucleus, the AHR/ARNT heterodimer binds to xenobiotic response elements (XREs) located in the 5’ flanking region of the target genes and then recruits the other components of the transcription initiation complex machinery. These XREs contain an invariant 5’-GCGTG-3’ core sequence recognized by AHR and ARNT heterodimer (Safe S. , 2001) . Alternatively, the AHR can also behave as a coactivator for the rat CYP1A2 gene where it associates with a binding factor that binds an enhancer sequence named XREII (Sogawa, et al., 2004). Finally, the AHR/ARNT dimerization and subsequent binding to the DNA leads to the de novo transcription of AHR target genes (Figure 1.2a).
