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

Abstract

Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are ligand-activated transcription factors that regulate the expression of drug metabolizing enzymes and drug transporters. Since their discoveries, they have been studied as important factors for regulating 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 pollutants. Therefore, PXR and CAR can respond to an enormous abundance of stimuli, resulting in significant shifts in metabolic programs and physiological homeostasis. Naturally, PXR and CAR have been implicated 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 mechanisms 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 molecule ligands. To effectively convey the impact of newly emerging research, we have arranged five diverse and representative key recent advances, four specific challenges, and four perspectives on future directions. SIGNFICANCE 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.

Epigenetic Mechanisms Contribute to Intraindividual Variations of Drug Metabolism Mediated by Cytochrome P450 Enzymes

“…A recent review has summarized a journey of rewards of xenobiotic receptors for their discovery stories (Xie, 2022). PXR and CAR are transcription factors and have since been defined as master regulators of xenobiotic responses through their transcriptional regulation of drug-metabolizing enzymes and transporters, including CYPs (Poudel et al, 2022). Activation of PXR and CAR is also associated with the development of numerous metabolic diseases (Zhang et al, 2022).…”

Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma

“…PXR also exhibits antiinflammatory and anti-fibrosis effects in the intestines 30 . Meanwhile, CAR, through a different protective mechanism, facilitates BA detoxification in the hepatocytes of CA-treated mice with Fxr and Pxr deficiencies 31,32 . CAR also functions locally in intestinal CD4 + effector T cells, by contributing to BA detoxification and inflammation resolution by upregulating the anti-inflammatory cytokine interleukin (IL)-10 and BA-detoxifying enzymes and transporters 25 .…”

Filling the Blank Space: Branched 4-Nonylphenol Isomers Are Responsible for Robust Constitutive Androstane Receptor (CAR) Activation by Nonylphenol

“…NPs have also been reported as highly effective activators not only of rodent Constitutive Androstane Receptor (CAR, NR1I3) but also of human and rodent Pregnane X Receptor (PXR, NR1I2). CAR is one of the main drug- and xenobiotic-responsive transcription factors regulating the expression of detoxification enzymes, conjugation enzymes, and transporters involved in the elimination of endogenous and exogenous substances, such as bilirubin, bile acids, and xenobiotics. , Additionally, CAR has an important role in glucose and lipid metabolism, as well as in endobiotic metabolism of steroid hormones, , and its modulation may offer therapeutic intervention in some metabolic diseases . Many environmental toxicants or industrial chemicals as well as some drugs have been identified as CAR activators …”

“…6,12 Additionally, CAR has an important role in glucose and lipid metabolism, as well as in endobiotic metabolism of steroid hormones, 13,14 and its modulation may offer therapeutic intervention in some metabolic diseases. 15 Many environ-mental toxicants or industrial chemicals as well as some drugs have been identified as CAR activators. 16 CAR has a typical nuclear receptor structure consisting of the DNA-binding domain (DBD) connected to the ligandbinding domain (LBD, Figure 1A,B) via a hinge region.…”