title: Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions.
abstract: Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-αplay important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and microfluidic organs-on-chips, which mimic the physiology of a multicellular environment, will likely replace the current cell-based workflow.
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245; William Carey University College of Osteopathic Medicine, 498 Tucsan Ave, Hattiesburg, Mississipi 39401.
authors.forename: Chandra
authors.initials: C
authors.lastname: Prakash
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245; University of Texas at Austin, 2100 Comal Street, Austin, Texas 78712.
authors.forename: Baltazar
authors.initials: B
authors.lastname: Zuniga
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245.
authors.forename: Chung Seog
authors.initials: CS
authors.lastname: Song
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245.
authors.forename: Shoulei
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245.
authors.forename: Jodie
authors.initials: J
authors.lastname: Cropper
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245.
authors.forename: Sulgi
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, Texas Research Park, 15355 Lambda Drive, San Antonio, Texas 78245; South Texas Veterans Health Care System, Audie L Murphy VA Hospital, 7400 Merton Minter Boulevard, San Antonio, Texas 78229.
authors.forename: Bandana
authors.initials: B
authors.lastname: Chatterjee
keywords: CAR; Drug interactions; Drug screening; Epigenetics; Gene induction; Genetic polymorphism; Nuclear receptors; PXR; Phase 0-III mediators; Xenobiotic-response element