Regulation of Nuclear Receptors PXR and CAR by Small Molecules and Signal Crosstalk: Roles in Drug Metabolism and Beyond

Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are ligand-activated transcription factors that regulate the ex-pression of drug metabolizing enzymes and drug transporters. Since their discoveries, they have been studied as important factors for reg-ulating processes related to drug efficacy, drug toxicity, and drug -drug interactions. However, their vast ligand-binding profiles extend into additional spaces, such as endogenously produced chemicals, microbiome metabolites, dietary compounds, and environmental pol-lutants. Therefore, PXR and CAR can respond to an enormous abun-dance of stimuli, resulting in significant shifts in metabolic programs and physiologic homeostasis. Naturally, PXR and CAR have been im-plicated in various diseases related to homeostatic perturbations, such as inflammatory bowel disorders, diabetes, and certain cancers. Recent findings have injected the field with new signaling mecha-nisms and tools to dissect the complex PXR and CAR biology and have strengthened the potential for future PXR and CAR modulators in the clinic. Here, we describe the historical and ongoing importance of PXR and CAR in drug metabolism pathways and how this history has evolved into new mechanisms that regulate and are regulated by these xenobiotic receptors, with a specific focus on small mole-cule ligands. To effectively convey the impact of newly emerging re-search, we have arranged five diverse and representative key recent advances, four specific challenges, and four perspectives on future directions.SIGNIFICANCE STATEMENTPXR and CAR are key transcription factors that regulate homeostatic detoxification of the liver and intestines. Diverse chemicals bind to these nuclear receptors, triggering their transcriptional tuning of the cellular metabolic response. This minireview revisits the importance of PXR and CAR in pharmaceutical drug responses and highlights recent results with implications beyond drug metabolism.

Automated summary

PXR and CAR are ligand-activated transcription factors that regulate drug metabolizing enzymes and transporters. They not only play important roles in drug efficacy, toxicity, and interactions, but also respond to a wide range of stimuli and are implicated in various diseases. Recent research has provided new insights into their biology and potential clinical applications.