Abstract
Cells adapt to an exposure to xenobiotics by upregulating the biosynthesis of proteins involved in xenobiotic metabolism. This is achieved largely via activation of cellular xenosensors that modulate gene expression. Biotransformation of xenobiotics frequently comes with the generation of reactive oxygen species (ROS). ROS, in turn, are known modulators of signal transduction processes. FOXO (forkhead box, class O) transcription factors are among the proteins deeply involved in the cellular response to stress, including oxidative stress elicited by the formation of ROS. On the one hand, FOXO activity is modulated by ROS, while on the other, FOXO target genes include many that encode antioxidant proteins – thereby establishing a regulatory circuit. Here, the role of ROS and of FOXOs in the regulation of xenosensor transcriptional activities will be discussed. Constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), arylhydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) all interact with FOXOs and/or ROS. The two latter not only fine-tune the activities of xenosensors but also mediate interactions between them. As a consequence, the emerging picture of an interplay between xenosensors, ROS and FOXO transcription factors suggests a modulatory role of ROS and FOXOs in the cellular adaptive response to xenobiotics.
Highlights
Exposure of mammalian cells to xenobiotics – i.e., compounds that are “foreign” to the organism of interest, such as toxins, metal ions, drugs, phytochemicals – elicits responses ranging from signaling and adaptation to cell death
Following a discussion of the modulation of FOXO signaling by reactive oxygen species (ROS), we will provide examples of xenosensors directly targeted by xenobiotics (CAR, pregnane X receptor (PXR), peroxisome proliferatoractivated receptor (PPAR), arylhydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2)) and delineate their relation with ROS and FOXOs
Exposure of cells to xenobiotics comes with an activation of xenosensors, such as nuclear receptor xenosensors (e.g., Constitutive androstane receptor (CAR), PXR, PPARs), AhR or Nrf2
Summary
Exposure of mammalian cells to xenobiotics – i.e., compounds that are “foreign” to the organism of interest, such as (environmental) toxins, metal ions, drugs, phytochemicals – elicits responses ranging from signaling and adaptation to cell death. Cells react to an exposure to xenobiotics by upregulating the formation of the xenobiotic metabolism machinery, i.e. of proteins involved in the above-mentioned phases of biotransformation This adaptive cellular response is largely due to the interaction of xenobiotics with signaling cascades and transcriptional regulators, i.e. Electron transfer to molecular oxygen will result in the generation of superoxide and derivatives thereof, such as hydrogen peroxide These ROS (this generic term will be used here when referring to superoxide and/or hydrogen peroxide) are known modulators of cellular signaling processes by interfering with signaling cascades at several levels, including at the level of transcriptional regulators. The purpose of this article is to provide a brief overview on the interplay between xenosensors, ROS and FOXO transcription factors in regulating the cellular response to an exposure to xenobiotics. Following a discussion of the modulation of FOXO signaling by ROS, we will provide examples of xenosensors directly targeted by xenobiotics (CAR, PXR, PPARs, AhR and Nrf2) and delineate their relation with ROS and FOXOs
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