Pharmacogenomic Variability in Drug Metabolism: From Nuclear Receptors to Clinical Enzyme Regulation

The regulation of drug-metabolizing enzymes (DMEs) is governed by nuclear receptors (NRs) — including PXR, CAR, AhR, FXR, and PPARα — that sense xenobiotic and endobiotic signals and directly control the transcription of cytochrome P450 enzymes, phase II conjugating enzymes, and drug transporters. Pharmacogenomic variability adds a critical layer of complexity to this regulatory landscape. Genetic polymorphisms in both NR genes and their DME targets — spanning CYP2D6, CYP2C9, CYP2C19, CYP3A4/5, UGT1A1, and TPMT — create substantial inter-individual differences in enzyme activity, leading to altered drug clearance, adverse reactions, or therapeutic failure. NR activity is further shaped by epigenetic modifications, inflammatory signaling, diet, and the gut microbiome, generating metabolic phenotypes that genotype alone cannot fully predict. Despite growing mechanistic insight, the clinical translation of NR biology into pharmacogenomic practice remains limited.This Research Topic aims to bridge molecular pharmacology and clinical practice by consolidating evidence on how nuclear receptors regulate DME expression and how pharmacogenomic variability modulates this regulation at the individual and population level. It seeks to identify novel regulatory targets and biomarkers that could advance genotype-guided dosing strategies.Topics of interest include, but are not limited to:- NR-mediated regulation of CYPs and phase II enzymes- Genetic variants in NR genes and functional consequences on DME expression- Drug-drug-gene interactions via nuclear receptor activation or suppression- Epigenetic, inflammatory, and microbiome modulation of NR-DME axes- Population-level pharmacogenomic variability in NR signaling pathways- Computational and translational approaches to modeling NR-driven metabolic variability- Clinical implementation of NR pharmacogenomics in dosing guidelines and decision supportPlease note: If patient data are analyzed, a comprehensive description of the patients including sex, age, diagnostic criteria, inclusion and exclusion criteria, disease stage, therapy received, comorbidities as well as additional clinical information and assessment of clinical response/effects should be included. If genetic, proteomics, metabolomics, or other omics data are analyzed, a comprehensive description of the methods and the rationale for selecting the specific data studied should be provided. Studies related to natural compounds, herbal extracts, or traditional medicine products, are outside the scope of the Specialty Section Pharmacogenetics & Pharmacogenomics, and should instead be submitted to the specialty section of Ethnopharmacology. Studies solely based on the analysis of public databases or published evidence, with no further experimental insights or insufficient experimental validation, will not be included in this Research Topic.Articles should fit into the Journal’s mission & scope. Further information on the Journal’s scope can be accessed following the link https://www.frontiersin.org/journals/pharmacology/about Topic editors: Andre Weber, Daotai Nie Source: https://www.frontiersin.org/research-topics/83663/pharmacogenomic-variability-in-drug-metabolism-from-nuclear-receptors-to-clinical-enzyme-regulation