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-α play 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.
Highlights
Drug metabolism, which occurs primarily in the liver and intestine, refers to the enzymatic modification and subsequent disposal of medicinally active compounds, originating either endogenously or exogenously
We describe various classes of drug-metabolizing enzymes (DMEs) and transporters, present an overview of the molecular underpinnings for nuclear receptor (NR)-mediated genetic and epigenetic regulation of ADME genes and consider roles for various NRs and their target genes in differential drug response
Regulation of CYP1B1 and CYP3A4 messenger RNA (mRNA) by miR-27b; CYP2E1 mRNA by miR-378; the MDR1 transporter by miR-451; and the BCRP transporter by miR328, miR-519C, miR-520h underscores the impact that micro RNAs (miRNAs) may have on drug metabolism and disposition, provided these miRNA-dependent regulations are upheld in vivo
Summary
Drug metabolism, which occurs primarily in the liver and intestine, refers to the enzymatic modification and subsequent disposal of medicinally active compounds, originating either endogenously (as steroids, neurotransmitters, metabolic products like bile acids) or exogenously (as natural products or synthetic/semi-synthetic chemicals). Drug metabolism and disposition is coordinated by an array of liver- and intestine-expressed drug-metabolizing enzymes (DMEs) and drug-transporting proteins whose tissue abundance is transcriptionally regulated by specific nuclear receptors (NRs), which are ligandactivated transcription factors [1]. Of the 48 distinct receptors comprising the NR superfamily in humans, pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are primary transcriptional regulators of the genes involved in the metabolism and elimination of drugs/drug metabolites [2,3,4]. We describe various classes of DMEs and transporters, present an overview of the molecular underpinnings for NR-mediated genetic and epigenetic regulation of ADME genes and consider roles for various NRs (especially PXR/CAR/VDR) and their target genes in differential drug response. End metabolites cleared via biliary excretion and/or Efflux urinary excretion transporter
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