Abstract
The aryl hydrocarbon receptor (AhR) mediates a variety of biological responses to ubiquitous environmental pollutants. In this study, the effects of administration of β-naphthoflavone (BNF), a potent AhR ligand, on the expression of AhR-dependent genes were examined by microarray and qPCR analysis in both, differentiated and undifferentiated HepaRG cell lines. To prove that BNF-induced changes of investigated genes were indeed AhR-dependent, we knock down the expression of AhR by stable transfection of HepaRG cells with shRNA. Regardless of genetical identity, our results clearly demonstrate different expression profiles of AhR-dependent genes between differentiated and undifferentiated HepaRG cells. Genes involved in metabolism of xenobiotics constitute only minute fraction of all genes regulated by AhR in HepaRG cells. Participation of AhR in induction of expression of genes associated with regulation of apoptosis or involved in cell proliferation as well as AhR-dependent inhibition of genes connected to cell adhesion could support suggestion of involvement of AhR not only in initiation but also in progression of carcinogenesis. Among the AhR-dependent genes known to be involved in metabolism of xenobiotics, cytochromes P4501A1 and 1B1 belong to the most inducible by BNF. On the contrary, expression of GSTA1 and GSTA2 was significantly inhibited after BNF treatment of HepaRG cells. Among the AhR-dependent genes that are not involved in metabolism of xenobiotics SERPINB2, STC2, ARL4C, and TIPARP belong to the most inducible by BNF. Our results imply involvement of Ah receptor in regulation of CYP19A1, the gene-encoding aromatase, and an enzyme responsible for a key step in the biosynthesis of estrogens.
Highlights
The aryl hydrocarbon receptor is a ligand-dependent transcription factor that mediates a variety of biological responses to ubiquitous environmental pollutants such as polycyclic aromatic hydrocarbons (PAH) and chlorinated dibenzo-pdioxins [1]
Genetic variations in the aryl hydrocarbon receptor (AhR) lead to significant differences in sensitivity to biochemical and carcinogenic effects of PAHs, TCDD, and related compounds [50]
Since late fifties till the end of twentieth century, most aspects of AhR function were contributed to its ability to induce enzymes responsible for metabolism of xenobiotic, drugs, and carcinogens [1, 51]
Summary
The aryl hydrocarbon receptor is a ligand-dependent transcription factor that mediates a variety of biological responses to ubiquitous environmental pollutants such as polycyclic aromatic hydrocarbons (PAH) and chlorinated dibenzo-pdioxins [1]. Despite the variability observed between experiments aiming to discover AhR-dependent genes, a small subset of AhR target genes, including CYP1A1, CYP1A2, CYP1B1, NQO1, ALAH3A1, UGT1A, and GSTA1, are commonly upregulated following AhR activation These genes encode phase I and phase II xenobiotic-metabolizing enzymes, which function to metabolize activating compounds and provide a vital role in the detoxification of xenobiotics [2,3,4,5]. These enzymes metabolize many of their substrates to more soluble and excretable products, but as the classic example of benzo[a]pyrene shows, the same enzymes are responsible for activation of substrates to ultimate carcinogenic metabolites. Functional analysis of AhR knockout mice revealed that AhR is involved in lethality, teratogenesis, immunotoxicity, hepatotoxicity, and tumor promotion caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [11,12,13,14,15]
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