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  1. Article ; Online: Regulation of PXR in drug metabolism: chemical and structural perspectives.

    Gee, Rebecca R Florke / Huber, Andrew D / Chen, Taosheng

    Expert opinion on drug metabolism & toxicology

    2024  Volume 20, Issue 1-2, Page(s) 9–23

    Abstract: Introduction: Pregnane X receptor (PXR) is a master xenobiotic sensor that transcriptionally controls drug metabolism and disposition pathways. PXR activation by pharmaceutical drugs, natural products, environmental toxins, etc. may decrease drug ... ...

    Abstract Introduction: Pregnane X receptor (PXR) is a master xenobiotic sensor that transcriptionally controls drug metabolism and disposition pathways. PXR activation by pharmaceutical drugs, natural products, environmental toxins, etc. may decrease drug efficacy and increase drug-drug interactions and drug toxicity, indicating a therapeutic value for PXR antagonists. However, PXR's functions in physiological events, such as intestinal inflammation, indicate that PXR activators may be useful in certain disease contexts.
    Areas covered: We review the reported roles of PXR in various physiological and pathological processes including drug metabolism, cancer, inflammation, energy metabolism, and endobiotic homeostasis. We then highlight specific cellular and chemical routes that modulate PXR activity and discuss the functional consequences. Databases searched and inclusive dates: PubMed, 1 January 1980 to 10 January 2024.
    Expert opinion: Knowledge of PXR's drug metabolism function has helped drug developers produce small molecules without PXR-mediated metabolic liabilities, and further understanding of PXR's cellular functions may offer drug development opportunities in multiple disease settings.
    MeSH term(s) Humans ; Pregnane X Receptor/metabolism ; Receptors, Steroid/metabolism ; Inactivation, Metabolic ; Inflammation
    Chemical Substances Pregnane X Receptor ; Receptors, Steroid
    Language English
    Publishing date 2024-01-28
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2214462-6
    ISSN 1744-7607 ; 1742-5255
    ISSN (online) 1744-7607
    ISSN 1742-5255
    DOI 10.1080/17425255.2024.2309212
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6264: Show issues Location:
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  2. Article ; Online: Hormonal Imbalances in Prader-Willi and Schaaf-Yang Syndromes Imply the Evolution of Specific Regulation of Hypothalamic Neuroendocrine Function in Mammals.

    Hoyos Sanchez, Maria Camila / Bayat, Tara / Gee, Rebecca R Florke / Fon Tacer, Klementina

    International journal of molecular sciences

    2023  Volume 24, Issue 17

    Abstract: The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of which are affected in patients with Prader-Willi (PWS) and Schaaf-Yang syndrome (SYS) ...

    Abstract The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of which are affected in patients with Prader-Willi (PWS) and Schaaf-Yang syndrome (SYS). PWS is caused by paternal deletion, maternal uniparental disomy, or imprinting defects that lead to loss of expression of a maternally imprinted region of chromosome 15 encompassing non-coding RNAs and five protein-coding genes; SYS patients have a mutation in one of them,
    MeSH term(s) Animals ; Syndrome ; Anxiety ; Hypothalamus ; Mammals/genetics ; Neurosecretory Systems
    Language English
    Publishing date 2023-08-23
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms241713109
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: PXR-mediated idiosyncratic drug-induced liver injury: mechanistic insights and targeting approaches.

    Wang, Jingheng / Bwayi, Monicah / Gee, Rebecca R Florke / Chen, Taosheng

    Expert opinion on drug metabolism & toxicology

    2020  Volume 16, Issue 8, Page(s) 711–722

    Abstract: Introduction: The human liver is the center for drug metabolism and detoxification and is, therefore, constantly exposed to toxic chemicals. The loss of liver function as a result of this exposure is referred to as drug-induced liver injury (DILI). The ... ...

    Abstract Introduction: The human liver is the center for drug metabolism and detoxification and is, therefore, constantly exposed to toxic chemicals. The loss of liver function as a result of this exposure is referred to as drug-induced liver injury (DILI). The pregnane X receptor (PXR) is the primary regulator of the hepatic drug-clearance system, which plays a critical role in mediating idiosyncratic DILI.
    Areas covered: This review is focused on common mechanisms of PXR-mediated DILI and on
    Expert opinion: DILI can be caused by many factors, and PXR is clearly linked to DILI. Although emerging data illustrate how PXR mediates DILI and how PXR activity can be modulated, many questions concerning the development of effective PXR modulators remain. Future research should be focused on determining the mechanisms regulating PXR functions in different cellular contexts.
    MeSH term(s) Animals ; Chemical and Drug Induced Liver Injury/physiopathology ; Drug Development ; Drug-Related Side Effects and Adverse Reactions/physiopathology ; Humans ; Models, Biological ; Pregnane X Receptor/antagonists & inhibitors ; Pregnane X Receptor/metabolism
    Chemical Substances Pregnane X Receptor
    Language English
    Publishing date 2020-06-16
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2214462-6
    ISSN 1744-7607 ; 1742-5255
    ISSN (online) 1744-7607
    ISSN 1742-5255
    DOI 10.1080/17425255.2020.1779701
    Database MEDical Literature Analysis and Retrieval System OnLINE

    Full text online

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  4. Article ; Online: A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR.

    Huber, Andrew D / Poudel, Shyaron / Wu, Jing / Miller, Darcie J / Lin, Wenwei / Yang, Lei / Bwayi, Monicah N / Rimmer, Mary Ashley / Gee, Rebecca R Florke / Seetharaman, Jayaraman / Chai, Sergio C / Chen, Taosheng

    Nucleic acids research

    2023  Volume 52, Issue 4, Page(s) 1661–1676

    Abstract: Bromodomain and extraterminal (BET) proteins are extensively studied in multiple pathologies, including cancer. BET proteins modulate transcription of various genes, including those synonymous with cancer, such as MYC. Thus, BET inhibitors are a major ... ...

    Abstract Bromodomain and extraterminal (BET) proteins are extensively studied in multiple pathologies, including cancer. BET proteins modulate transcription of various genes, including those synonymous with cancer, such as MYC. Thus, BET inhibitors are a major area of drug development efforts. (+)-JQ1 (JQ1) is the prototype inhibitor and is a common tool to probe BET functions. While showing therapeutic promise, JQ1 is not clinically usable, partly due to metabolic instability. Here, we show that JQ1 and the BET-inactive (-)-JQ1 are agonists of pregnane X receptor (PXR), a nuclear receptor that transcriptionally regulates genes encoding drug-metabolizing enzymes such as CYP3A4, which was previously shown to oxidize JQ1. A PXR-JQ1 co-crystal structure identified JQ1's tert-butyl moiety as a PXR anchor and explains binding by (-)-JQ1. Analogs differing at the tert-butyl lost PXR binding, validating our structural findings. Evaluation in liver cell models revealed both PXR-dependent and PXR-independent modulation of CYP3A4 expression by BET inhibitors. We have characterized a non-BET JQ1 target, a mechanism of physiological JQ1 instability, a biological function of (-)-JQ1, and BET-dependent transcriptional regulation of drug metabolism genes.
    MeSH term(s) Azepines/chemistry ; Azepines/pharmacology ; Cell Line, Tumor ; Cell Proliferation ; Cytochrome P-450 CYP3A/genetics ; Nuclear Proteins/metabolism ; Pregnane X Receptor/chemistry ; Proto-Oncogene Proteins c-myc/genetics ; Receptors, Cytoplasmic and Nuclear ; Triazoles/chemistry ; Triazoles/pharmacology ; Humans
    Chemical Substances (+)-JQ1 compound ; Azepines ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; Nuclear Proteins ; Pregnane X Receptor ; Proto-Oncogene Proteins c-myc ; Receptors, Cytoplasmic and Nuclear ; Triazoles
    Language English
    Publishing date 2023-12-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkad1175
    Database MEDical Literature Analysis and Retrieval System OnLINE

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