Cellular adaptation to xenobiotics: Interplay between xenosensors, reactive oxygen species and FOXO transcription factors

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.