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Drug-induced cis-regulatory elements in human hepatocytes affect molecular phenotypes associated with drug efficacy and adverse reactions

ABSTRACT: We conducted a quantitative assessment of drug-inducible cis-regulatory elements (CREs) based on transcription initiation profiling of mRNAs and noncoding RNAs, including enhancer RNAs, by using CAGE (Cap Analysis of Gene Expression). Candidate CREs were identified in a hepatocellular carcinoma HepG2 cell line with stable expression of drug-responsive transcription factor pregnane X receptor (PXR) .

ORGANISM(S): Homo sapiens

PROVIDER: GSE272109 | GEO | 2024/07/24

REPOSITORIES: GEO

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Effect of PCN on CAR and PXR regulated genes involved in circadian rhythm, drug metabolism and cholesterol homeostasis

Project description:The nuclear receptor PXR (Pregnane X rreceptor) mediates the effects of pregnenolone-16alpha-carbonitrile (PCN) on gene transcription. The relative role of PXR and also CAR to the induction response by PCN was studied on cDNA arrays containing 320 (Steroltalk V2) genes (genes involved in cyrcadian rhythm, drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PCN for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments show the complex role of PXR receptor in the expression of genes involved in cyrcadian rhythm, drug metabolism and cholesterol biosynthesis.

2008-11-13 | GSE12537 | GEO

Effect of phenobarbital on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis

Project description:The nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor) mediate the effects of phenobarbital (PB) on gene transcription. To investigate the relative role of CAR and PXR in the induction response, cDNA arrays were generated containing 120 genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PB for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments unexpectedly revealed that if CAR and PXR are deleted, PB increases the expression of several other nuclear receptors and genes involved in drug metabolism and cholesterol biosynthesis.

2008-08-23 | GSE12489 | GEO

Effect of PCN on CAR and PXR regulated genes involved in circadian rhythm, drug metabolism and cholesterol homeostasis

Project description:The nuclear receptor PXR (Pregnane X rreceptor) mediates the effects of pregnenolone-16alpha-carbonitrile (PCN) on gene transcription. The relative role of PXR and also CAR to the induction response by PCN was studied on cDNA arrays containing 320 (Steroltalk V2) genes (genes involved in cyrcadian rhythm, drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PCN for gene expression within the European Framework V program âSteroltalkâ (www.steroltalk.net). Results from these experiments show the complex role of PXR receptor in the expression of genes involved in cyrcadian rhythm, drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 40mg/kg PCN or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the PCN treated ones and hybridized to Steroltalk V2 arrays.

2010-05-16 | E-GEOD-12537 | biostudies-arrayexpress

Effect of phenobarbital on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis

2008-08-23 | E-GEOD-12489 | biostudies-arrayexpress

The pregnane X receptor drives sexually dimorphic hepatic changes in lipid and xenobiotic metabolism in response to gut microbiota in mice

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2020-08-26 | GSE156837 | GEO

Transcriptional profiling of liver from wild type and PXR-null mice treated with PCN

Project description:Many environmentally-relevant chemicals and drugs activate the nuclear receptor pregnane X receptor (PXR). Activation of PXR can lead to increases in liver weight in part through hepatocyte replication similar to a large number of compounds that activate other nuclear receptors such as the peroxisome proliferator-activated receptor alpha and the constitutive activated receptor (CAR). PXR controls the expression of a large battery of genes involved in xenobiotic metabolism. Identification of genes that are accurate predictors of PXR activation would be useful in high-throughput screens to assess potential toxicity and drug-drug interactions. Here, we identified PXR-dependent genes in the mouse liver after exposure to pregnenolone 16alpha-carbinonitrile (PCN), a chemical that is often used as a model PXR agonist.

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Expression data from skin of patients with adverse drug reactions (ADRs)

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2019-02-01 | GSE121421 | GEO

Transcription profiling of human liver in response to flucloxacilin-induced liver injury

Project description:Drug-induced liver injury (DILI) due to flucloxacillin is a rare but serious complication of treatment with this antimicrobial. The genetic basis of susceptibility is poorly understood as is the underlying molecular mechanism for disease. There is some evidence that flucloxacillin is a pregnane X receptor (PXR) agonist. The current study was concerned with investigating the relevance of PXR to flucloxacillin toxicity and with the identification of genes changing in expression in response to flucloxacillin.

2009-12-01 | E-MEXP-2128 | biostudies-arrayexpress

Adverse drug reactions in drug information databases: does presentation affect interpretation?

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| S-EPMC6919994 | biostudies-literature

Drug-induced cis-regulatory elements in human hepatocytes affect molecular phenotypes associated with drug efficacy and adverse reactions

Project description:Drug-induced cis-regulatory elements in human hepatocytes affect molecular phenotypes associated with drug efficacy and adverse reactions

| PRJNA1135139 | ENA

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