Abstract
To appraise how evolutionary processes, such as gene duplication and loss, influence an organism’s xenobiotic sensitivity is a critical question in toxicology. Of particular importance are gene families involved in the mediation of detoxification responses, such as members of the nuclear receptor subfamily 1 group I (NR1I), the pregnane X receptor (PXR), and the constitutive androstane receptor (CAR). While documented in multiple vertebrate genomes, PXR and CAR display an intriguing gene distribution. PXR is absent in birds and reptiles, while CAR shows a tetrapod-specific occurrence. More elusive is the presence of PXR and CAR gene orthologs in early branching and ecologically-important Chondrichthyes (chimaeras, sharks and rays). Therefore, we investigated various genome projects and use them to provide the first identification and functional characterization of a Chondrichthyan PXR from the chimaera elephant shark (Callorhinchus milii, Holocephali). Additionally, we substantiate the targeted PXR gene loss in Elasmobranchii (sharks and rays). Compared to other vertebrate groups, the chimaera PXR ortholog displays a diverse expression pattern (skin and gills) and a unique activation profile by classical xenobiotic ligands. Our findings provide insights into the molecular landscape of detoxification mechanisms and suggest lineage-specific adaptations in response to xenobiotics in gnathostome evolution.
Highlights
Nuclear receptors (NRs) are central constituents of animal endocrine systems
pregnane X receptor (PXR) and constitutive androstane receptor (CAR) were originally identified as xenobiotic sensors, since they regulate genes involved in drug metabolism such as phase I cytochrome P450 (e.g., CYP3A4, CYP2B6 and CYP2C), phase II transferases (e.g., uridine 5 -diphospho(UDP)-glucuronosyl transferase and glutathione-S-transferase), and drug transporters
CmiPXR shares around 70% of its sequence identity to other PXR-DNA-binding domain (DBD) (Figure 1B), with the ligand binding domain (LBD) identity values displaying significantly lower values (Figure 1B)
Summary
Nuclear receptors (NRs) are central constituents of animal endocrine systems. These ligand-dependent sensors act as transcription factors, regulating key physiological processes including metabolism, development, reproduction and nutrient utilization [1]. Two critical components of the vertebrate’s “chemical defensome” are the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) [4]. These are part of nuclear receptor subfamily 1 group I (NR1I), which includes the vitamin D receptor (VDR). PXR and CAR were originally identified as xenobiotic sensors, since they regulate genes involved in drug metabolism such as phase I cytochrome P450 (e.g., CYP3A4, CYP2B6 and CYP2C), phase II transferases (e.g., uridine 5 -diphospho(UDP)-glucuronosyl transferase and glutathione-S-transferase), and drug transporters
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