4SC-202 br Discussion AhR is a receptor that binds to

Discussion AhR is a receptor that binds to a great variety of lipophilic compounds, in particular those containing at least one aromatic ring (Abel and Haarmann-Stemmann, 2010, Guyot et al., 2013, Hahn, 2002). The main known function of this receptor is to induce the metabolism of these compounds by phase I and phase II 4SC-202 in order to render them more hydrophilic and thus facilitate their elimination (Köhle and Bock, 2007). Several polycyclic/polychlorinated hydrocarbons, in particular PCDD, activate AhR with a high potency and induce toxic symptoms to mammals including humans (Van den Berg et al., 1994). The skin is a target of these compounds and develops a myriad of small hamartoma parallel to the atrophy of sebaceous glands. It was thus believed that AhR activation was related to dioxin toxicity (Bock and Kohle, 2009, Bohonowych and Denison, 2007, Van den Berg et al., 1994). We now know that a growing list of natural compounds chemically unrelated to dioxins and found for instance in vegetables activate AhR without inducing any toxicity and may on the contrary exert beneficial effects to human health (Bock and Kohle, 2009). On the other hand, other chemicals such as kinase inhibitors given as chemotherapeutic agents induce a chloracne-like syndrome without activating AhR (Butts and Jatoi, 2010, Nardone et al., 2010). This is the case, for instance, for vemurafenib, an inhibitor of BRAF kinase carrying the V600E mutation, given to V600E-positive patients with a metastatic melanoma (Boussemart et al., 2013, Rinderknecht et al., 2013). It is important to bear in mind that activation of AhR does not necessarily mean an induction of genes; the presence of XRE in the promoter region of genes may be linked both to gene induction or repression. This was highlighted by our genomic analysis of V. Yushchenko, where many enzymes were highly repressed following acute TCDD intoxication (Saurat et al., 2012). In this context, some biological properties of dioxin may be linked to the repression of particular genes. These data compel us to rethink the mechanism of toxicity of dioxin-like compounds. Cross-talk between AhR and other nuclear receptors including estrogen receptors have been observed (Boverhof et al., 2006, Ohtake et al., 2003, Swedenborg and Pongratz, 2010), and might explain in part the diversity of biological actions mediated by AhR activation. Other signalling pathways activated by dioxins but not by non-chloracnegen AhR agonists, if they exist, may be a part of the explanation too. Finally the differences observed with AhR agonists regarding the kinetics of AhR binding, the mechanism of the modulation of gene expression and their biological half-lives might also influence their biological properties (Beischlag et al., 2008, Bohonowych and Denison, 2007). TCDD, for instance, has a biological half-life of several years, and has a very slow metabolism (Aylward et al., 2005, Geusau et al., 2001, Sorg et al., 2009). Regarding dioxin toxicity, many people are exposed to dioxin-like pollutants with very long biological half-lives and thus accumulate them in the body. We do not know what would be the impact of such a chronic exposure on human health and we definitely need sensitive biomarkers to detect an exposure to these persistent organic pollutants (Hu et al., 2007).
Conflict of interest statement
Introduction Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated through incomplete combustion of organic materials. Benzo[α]pyrene (BaP) is an extensively characterized, prototypical human and animal carcinogen commonly found in air, water, soil sediment and high temperature processed meats (Boffetta et al., 1997, Mastrangelo et al., 1996, Chemical agents and related occupations, 2012). A critical step in the induction of cancer by BaP is its bioactivation by phase I metabolizing enzymes − most notably CYP1A1 which is a member of the cytochrome P450 (CYP) 1A family regulated by the aryl hydrocarbon receptor (AhR) (Whitlock, 1999). The AhR-regulated cyp1a1 expression requires that AhR forming a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT) and AhR-ARNT complex binding to the upstream enhancer containing consensus dioxin-responsive element sequences (DRE, 5′-TNGCGTG-3′) for transcriptional activation of cyp1a1 expression (Dong et al., 1996).