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 xenobiotic-induced 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 a, 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.
CITATION STYLE
Men, S., & Wang, H. (2023, February 1). Phenobarbital in Nuclear Receptor Activation: An Update. Drug Metabolism and Disposition. American Society for Pharmacology and Experimental Therapy (ASPET). https://doi.org/10.1124/dmd.122.000859
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