Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

Prakash, Chandra; Zuniga, Baltazar; Song, Chung S.; Jiang, Shoulei; Cropper, Jodie; Park, Sul-Gi; Chatterjee, Bandana

doi:10.11131/2015/101178

Cited by 86 publications

(53 citation statements)

References 145 publications

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“…The exact mechanism remains unknown and may be related to various nuclear receptors and transcription factors. Similarly, certain medications and environmental toxins could lead to activation of nuclear receptor pathway, and could, therefore, influence the transporter expression . The underlying reason for death of our tissue donors is heterogeneous and so are the exposure of drugs and environmental toxins.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, certain medications and environmental toxins could lead to activation of nuclear receptor pathway, and could, therefore, influence the transporter expression. 44,45 The underlying reason for death of our tissue donors is heterogeneous and so are the exposure of drugs and environmental toxins. Yet, despite all these inevitable differences, significant changes in the expression levels by age were still observed.…”

Section: Potential Limitationsmentioning

confidence: 99%

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A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Cheung

Groen

Spaans

et al. 2019

Clin Pharma and Therapeutics

136

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Human renal membrane transporters play key roles in the disposition of renally cleared drugs and endogenous substrates, but their ontogeny is largely unknown. Using 184 human postmortem frozen renal cortical tissues (preterm newborns to adults) and a subset of 62 tissue samples, we measured the mRNA levels of 11 renal transporters and the transcription factor pregnane X receptor (PXR) with quantitative real-time polymerase chain reaction, and protein abundance of nine transporters using liquid chromatography tandem mass spectrometry selective reaction monitoring, respectively. Expression levels of p-glycoprotein, urate transporter 1, organic anion transporter 1, organic anion transporter 3, and organic cation transporter 2 increased with age. Protein levels of multidrug and toxin extrusion transporter 2-K and breast cancer resistance protein showed no difference from newborns to adults, despite age-related changes in mRNA expression. Multidrug and toxin extrusion transporter 1, glucose transporter 2, multidrug resistance-associated protein 2, multidrug resistance-associated protein 4 (MRP4), and PXR expression levels were stable. Using immunohistochemistry, we found that MRP4 localization in pediatric samples was similar to that in adult samples. Collectively, our study revealed that renal drug transporters exhibited different rates and patterns of maturation, suggesting that renal handling of substrates may change with age.

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Section: Discussionmentioning

confidence: 99%

Section: Potential Limitationsmentioning

confidence: 99%

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Cheung

Groen

Spaans

et al. 2019

Clin Pharma and Therapeutics

136

View full text Add to dashboard Cite

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“…Specific nuclear receptors regulate the expression of different P450 isoforms as well as other hepatic Phase II enzymes and transporters involved in xenobiotic metabolism, steroid synthesis, and detoxification. The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are particularly relevant to drug metabolism, acting as xenobiotic sensors to regulate the induction of CYP3A, CYP2B, and CYP2C subfamilies [11–14]. Upon direct or indirect binding of their ligands, these nuclear receptors translocate from the cytoplasm to the nucleus, where they facilitate the recruitment of chromatin remodelers and coactivators to promote the transcription of P450 genes [15].…”

Section: The Molecular Mechanisms Of Ddis Through Induction Of P450smentioning

confidence: 99%

Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-Drug Interactions in Adult Life

et al. 2017

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Purpose of review As the number of patients taking more than one medication concurrently continues to increase, predicting and preventing drug-drug interactions (DDIs) is now more important than ever. Administration of one drug can cause changes in the expression and activity of drug metabolizing enzymes (DMEs) and alter the efficacy or toxicity of other medications that are substrates for these enzymes, resulting in a DDI. In today’s medical practice, potential DDIs are evaluated based on the current medications a patient is taking with little regard to drugs the patient has been exposed to in the past. The purpose of this review is to discuss potential impacts of drug treatment at neonatal ages on the variability of drug metabolism and DDIs in adult life. Recent findings Existing evidence from the last thirty years has shown that exposure to certain xenobiotics during neonatal life has the potential to persistently alter DME expression through adult life. With recent advancements in the understanding of epigenetic regulation on gene expression, this phenomenon is resurfacing in the scientific community in hopes of defining possible mechanisms. Exposure to compounds that have the ability to bind nuclear receptors and trigger epigenetic modifications at neonatal and pediatric ages may have long-term, if not permanent, consequences on gene expression and DME activity. Summary The information summarized in this review should challenge the way current healthcare providers assess DDI potential and may offer an explanation to the significant interindividual variability in drug metabolism that is observed among patients.

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“…Activation of the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) by drugs and environmental pollutants induces the hepatic expression of genes involved in drug and energy metabolism (Prakash et al, 2015). This accelerates the disposition, and thereby reduces the efficacy, of numerous drugs, such as oral antiretrovirals, contraceptives, and immunosuppressants.…”

Section: Introductionmentioning

confidence: 99%

Health-Relevant Phenotypes in the Offspring of Mice Given CAR Activators Prior to Pregnancy

et al. 2018

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Hepatic induction in response to drugs and environmental chemicals affects drug therapies and energy metabolism. We investigated whether the induction is transmitted to the offspring. We injected 3-day- and 6-week-old F0 female mice with TCPOBOP, an activator of the nuclear receptor constitutive androstane receptor (CAR, NR1I3), and mated them 1-6 weeks afterward. We detected in the offspring long-lasting alterations of CAR-mediated drug disposition, energy metabolism, and lipid profile. The transmission to the first filial generation (F1) was mediated by TCPOBOP transfer from the F0 adipose tissue via milk, as revealed by embryo transfer, crossfostering experiments, and liquid chromatography-mass spectrometry analyses. The important environmental pollutant PCB153 activated CAR in the F1 generation in a manner similar to TCPOBOP. Our findings indicate that chemicals accumulating and persisting in adipose tissue may exert liver-mediated, health-relevant effects on F1 offspring simply via physical transmission in milk. Such effects may occur even if treatment has been terminated far ahead of conception. This should be considered in assessing developmental toxicity and in the long-term follow-up of offspring of mothers exposed to both approved and investigational drugs, and to chemicals with known or suspected accumulation in adipose tissue.

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Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

Cited by 86 publications

References 145 publications

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

A Comprehensive Analysis of Ontogeny of Renal Drug Transporters: mRNA Analyses, Quantitative Proteomics, and Localization

Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-Drug Interactions in Adult Life

Health-Relevant Phenotypes in the Offspring of Mice Given CAR Activators Prior to Pregnancy

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