Phenobarbital in Nuclear Receptor Activation: An Update

Abstract

Phenobarbital (PB) is a commonly prescribed anti-epileptic drug that can also benefit newborns from hyperbilirubinemia. Being the first drug demonstrating hepatic induction of cytochrome P450 (CYP), PB has since been broadly used as a model compound to study xenobioticinduced drug metabolism and clearance. Mechanistically, PB-mediated CYP induction is linked to a number of nuclear receptors such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and estrogen receptor α, with CAR being the predominant regulator. Unlike prototypical agonistic ligands, PB-mediated activation of CAR does not involve direct binding with the receptor. Instead, dephosphorylation of threonine 38 in the DNA-binding domain of CAR was delineated as a key signaling event underlying PB-mediated indirect activation of CAR.Further studies revealed that such phosphorylation sites appear to be highly conserved among most human nuclear receptors. Interestingly, while PB is a pan-CAR activator in both animals and humans, PB activates human but not mouse PXR. The species-specific role of PB in gene regulation is a key determinant of its implication in xenobiotic metabolism, drug-drug interactions, energy homeostasis, and cell proliferation. In this review, we summarize the recent progress in our understanding of PB-provoked transactivation of nuclear receptors with a focus on CAR and PXR. Significance statementExtensive studies using PB as a research tool have significantly advanced our understanding of the molecular basis underlying nuclear receptor-mediated drug metabolism, drug-drug interactions, energy homeostasis, and cell proliferation. In particular, CAR has been established as a cell signaling-regulated nuclear receptor in addition to ligand-dependent functionality. This mini-review highlights the mechanisms by which PB transactivates CAR and PXR.

Completion of the DrugMatrix Toxicogenomics Database using ToxCompl

“…Primidone is metabolized in vivo to phenobarbital [14], which activates the nuclear receptors CAR and PXR. This activation leads to an increased expression of Cyp2b1, Cyp2b2, and Cyp3a9 in the liver [74]. The predicted gene expression response from a treatment of Primidone at a dose of 750 mg/kg for 5 days, indicated an increased expression of all three of these genes (see Complete DrugMatrix application).…”

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

“…At a molecular level, when a drug, which can induce CYP expression, is taken up into a metabolic cell, it can serve as a ligand to bind to either PXR or CAR in its ligand binding domain. Binding of PXR or CAR by the drug can result in configuration change and activation of PXR or CAR in cytoplasm and subcellular translocation into the nucleus (Men et al, 2022). The DNA binding domain of PXR or CAR can recognize its DNA response elements in the promoter regions of some CYP genes to facilitate transcriptional regulation (Jana et al, 2007).…”