The response to a xenobiotic insult is mainly mediated by the bHLHPAS protein aryl hydrocarbon receptor (AhR) and the nuclear receptors SXR/PXR and CAR. They are therefore called xenosensors. The binding of toxic substances to these receptors results in the transcription of genes encoding enzymes involved in the metabolism and transport of xenobiotics and their metabolites. Coregulators play an important role in the signal transduction of AhR, SXR/PXR, and CAR. Many of these coregulators are also crucial for the signaling of the hormone receptors in the nuclear receptor family. Thus, in the presence of xenobiotics, the recruitment of coactivators to the xenosensors can lead to impaired hormonal signaling. This is one of the mechanisms that may explain endocrine disruption (impaired hormone response after chemical exposure), a phenomenon that has raised attention and concern during recent decades.
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