Role of the aryl hydrocarbon receptor in drug metabolism

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that regulates the transcription of certain key enzymes involved in the metabolism of xenobiotic substances including some drugs. The AhR can be activated by a wide range of classes of compounds (e.g. polycyclic aromatic hydrocarbons, benzimidazoles and flavonoids), and interacts with a number of other proteins, including nuclear hormone receptors such as the oestrogen and androgen receptors. Activation of the AhR antagonises the oestrogen receptor and can lead to modulation of its transcriptional activity; thus, activating the AhR may serve as a target for breast cancer therapy. Disruption of normal signalling by drug interactions with the AhR or downstream components of this pathway could result in adverse effects, such as the bioactivation of procarcinogens or the disruption of normal homeostasis. The cytochrome P450s CYP1A1, -1B1, -1A2 and -2S1 are regulated by the AhR, and they are all involved in the metabolism of endogenous substrates as well as xenobiotics. Polymorphisms in the AhR, or polymorphisms in enzymes regulated by the AhR, may cause variations in response to certain drugs in different individuals; this needs to be taken into consideration when administering drugs that interact with this pathway.

Impact of AhR, CYP1A1 and GSTM1 Genetic Polymorphisms on TP53 R273G Mutations in Individuals Exposed to Polycyclic Aromatic Hydrocarbons

“…Further, the metabolism of PAHs induces DNA damage and carcinogenesis which could be modulated by genetic variation (Shimizu et al, 2000;Jiang et al, 2005;Ramadoss et al, 2005;Chen et al, 2006). In this study, significant difference (p=0.02, 95%CI, 0.70-15.86) was observed in the R273G mutation in p53 exon 8 for the genetic polymorphisms of Lys/Arg for AhR.…”

Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24

“…In response to xenobiotics, the heterodimer of ARNT/AhR binds to xenobiotic response element of the target genes such as cytochrome P450 and UDP-glucuronosyltransferases, which are important enzymes for the detoxification or metabolic activation, to increase their expression (Köhle and Bock, 2007;Ramadoss et al, 2005). In addition, under a hypoxia condition, ARNT dimerizes with HIF1α to upregulate the expression of genes involved in angiogenesis and tumorigenesis (Ke and Costa, 2006).…”

The microbiome and its pharmacological targets: therapeutic avenues in cardiometabolic diseases

“…AhR agonists enter the cell by diffusion and bind to the cytosolic inactive AhR complex, comprised by heat shock protein 90 (hsp90), HBB X-associated protein 2 (XAP2) and protein 23 (p23) [43,44]. Upon binding, the bound complex is translocated into the nucleus, resulting in the recognition of xenobiotic responsive elements (XRE) and transcription of genes coding for detoxification enzymes (CYP1A1, CYP1A2 and CYP2S1) [43]. AhR was also shown to mediate inflammatory signalling through non-canonical pathways, activating NF-KB and AP-1 independently of AhR nuclear translocation [45].…”