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    • The results of cell culture models were further supported by

    2023-11-21

    The results of cell culture models were further supported by in vivo studies in mice treated with PXR and/or AhR agonists, PCN and β-NF. In these mice, AhR-regulated cyp1a1, and cyp1a2 were suppressed by PXR activation as determined by real time Q-PCR (Fig. 3). The level of PXR mRNA was not changed significantly by the treatment. However, there was a slight decrease of AhR mRNA level by PCN and β-NF co-treatment which is unlikely to account for the much larger decreases in expression of cyp1a1 and cyp1a2 (data not shown). The mouse liver tissues were further analyzed by Western blot and level of β-NF-induced expression of CYP1A1 protein was suppressed by PCN co-treatment (Fig. 3D). Crosstalk between signaling pathways is often regulated through direct protein–protein interaction. To analyze the AhR and PXR interaction, we performed co-immunoprecipitation assays and found that PXR was associated with AhR in HepG2 cells. We further analyzed the domains involved in the interaction by GST-pulldown assays. PXR N-terminal domains which include the activation domain and DNA binding domain preferentially interacted with the basic region of the AhR N-terminus. Although the AhR protein levels did not seem to be decreased by PXR (data not shown), the direct interaction between transcription factors may inhibit its association with consensus DNA sequences as demonstrated between PXR and NF-κB RelA (Gu et al., 2006). Consistent with this hypothesis we found that ligand-induced association of AhR with DNA sequences in the cyp1a1 regulatory regions was decreased by PXR activation in HepG2 A-1155463 − results consistent with the notion that PXR suppresses the AhR transcriptional activity. Interestingly, we found in the PXR null hepatocytes as well as in HepG2 cells, co-treatment with PCN and BaP resulted in significantly more DNA damages comparing with BaP treatment alone (Figs. 1C and 3F). This phenomenon was not observed in PXR+/+ hepatocytes suggesting in the absence of the PXR PCN is a DNA damaging xenobiotic compound. This observed was consistent with our earlier results using HepG2 cells (Naspinski et al., 2008). PAHs and their metabolites may activate different xenobiotic receptors/cytochrome P450 system leading to their bioactivation and ultimate metabolic elimination (Luckert et al., 1996). Many previous studies focused on the specificity of the PAHs as the receptor ligands for different receptor/enzyme systems. The crosstalk between xenobiotic sensors AhR and PXR through direct receptor interactions which alter the transcription of gene expression provides a new dimension in which the PAH metabolism can be regulated. In summary, we demonstrated in this study PXR activation suppressed AhR-regulated gene expression through preventing AhR from binding to target genes. This effect would lead to suppression of AhR-mediated biotransformation of BaP and DNA damage caused by the carcinogen (Fig. 7). This novel finding suggest a dual role of PXR in protecting the genome from BaP-induced DNA damage, i.e. metabolic detoxification of BaP and inhibition of AhR-regulated biotransformation of BaP from a procarcinogen to an ultimate carcinogen.
    Funding This work was supported, in part, by a NIEHS/NIH grant ES 09859 and an American Heart Association Grant 0355131Y to YT.
    Conflict of interest
    Acknowledgements
    Introduction Associations made in the past between the AHR and cancer have most often be made in the context of the production of mutagenic intermediates, DNA damage, and the subsequent generation of genetic mutations. In this regard, the AHR is well known, perhaps best known, for its transcriptional regulation of cytochrome P-450 genes encoding monooxygenases, e.g., CYP1A1, CYP1A2 and CYP1B1, which generate highly reactive epoxides from environmental chemical substrates. Indeed, the DNA adducts that are produced through AHR-regulated CYP1 enzymes have been used as biomarkers for chemical (e.g. polycyclic aromatic hydrocarbon/PAH) exposure and for increased risk of malignant transformation [1–3]. Consequently, it is clear that the AHR participates in what classically became known as tumor initiation through genotoxicity. However, the relatively straightforward mechanism of mutagenesis belies the myriad of pathways through which the AHR likely influences later steps in cancer progression. That is, environmental pollutants have long been known of being drivers of both cancer initiation and cancer progression through non-genotoxic mechanisms [4–6]. Here, we review the evidence for an ongoing role for the AHR in cancer aggression, in the presence or absence of its environmental ligands.