Xenobiotic Metabolism Signaling

Humans are exposed to numerous natural or synthetic chemical compounds, foreign to the human body and called xenobiotics. These include food additives, environmental pollutants, drugs, etc. Many xenobiotics can trigger cellular stress response, leading to cell proliferation, differentiation, apoptosis or necrosis. The body protects itself not only against potentially harmful xenobiotics, but also against toxic endogenous compounds and their metabolites, by inducing the expression of enzymes and transporters involved in their metabolism, elimination and/or detoxification. These enzymes, called drug or xenobiotic metabolizing enzymes (DMEs or XMEs) are divided into three groups: Phase I enzymes (CYP, ALDH, FMO) usually introduce a polar moiety into the xenobiotics. Phase II enzymes (UGT, GST, SULT) conjugate the xenobiotics to small hydrophilic endogenous molecules such as glucuronic acid, glutathione, sulfate, producing even more hydrophilic products. Phase III enzymes (MDR1, OATP2, MRP) are transporters that export xenobiotics or conjugates formed during phase II out of the cell. One particularity of these XMEs is their inducibility by their own substrates, through signaling cascades involving specific receptors (CAR, PXR, AHR) and MAPK-mediated activation of transcription factors (NRF2, MAF).Constitutive active receptor (CAR) is able to transactivate target genes in the absence of ligands. In the absence of activators, CAR is sequestred in cytoplasm as a complex with HSP90 and CCRP. Upon addition of an activator, CAR translocates into the nucleus, forms a heterodimer with RXRα and binds to several variants of the repeat motif, such as DR3, DR4, ER6 and ER8. Upon binding of an inverse agonist, the co-activator NCOA is dissociated from the CAR ligand-binding domain, leading to the transcriptional inhibition of CAR.The pregnane X receptor (PXR) localized in the nucleus, associates with the corepressor SMRT and remains transcriptionally inactive without a bound ligand. Upon ligand binding, PXR dissociates from SMRT and forms a heterodimer with RXRα. The PXR/RXRα complex recruits the coactivator NCOA and transactivates DR3, DR4, ER6 and ER8 elements upstream of the target metabolizing enzymes.The unliganded aryl hydrocarbon receptor (AHR) is retained in the cytoplasm in a complex consisting of chaperone proteins, such as HSP90, XAP2, and TEBP. Upon ligand binding, AHR dissociates from the complex and translocates to the nucleus, where it associates with ARNT. This heterodimer binds to the dioxin or xenobiotic response element (DRE or XRE) of metabolizing enzymes activating their transcription.The transcription of many phase II metabolizing enzymes as well as cellular defense enzymes is enhanced by the activation of the MAPK pathway, resulting in the activation of the transcription factor NRF2, which associates with MAF and binds to the antioxidant/electrophile response element (ARE/EpRE). In the end, the xenobiotics, through the activation of nuclear receptors and transcription factors enhance their own metabolism, leading to cell survival.