Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1202546 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31821812.fastq.gz | Fastqsanger.gz | |||
| SRR31821813.fastq.gz | Fastqsanger.gz | |||
| SRR31821814.fastq.gz | Fastqsanger.gz | |||
| SRR31821815.fastq.gz | Fastqsanger.gz | |||
| SRR31821816.fastq.gz | Fastqsanger.gz |
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Project description:Orally administered drugs are absorbed and metabolized in the intestine. In order to accurately predict pharmacokinetics in the intestine, it is essential to understand the intestinal expression profiles of genes related to drug absorption, distribution, metabolism, and excretion (ADME). However, in many previous studies, gene expression analysis in the intestine has been carried out using specimens from cancer patients. In this study, in order to obtain a more accurate gene expression profile, biopsy samples were collected from 14 patients under endoscopic observation and RNA-seq analysis was performed. Gene expression analysis of drug metabolizing enzymes (CYPs), non-CYP enzymes, nuclear receptors, drug conjugating enzymes (UGTs and SULTs), and apical and basolateral drug transporters was performed in biopsy samples from the duodenum, ileum, colon, and rectum. The proportions of the CYPs expressed in the ileum were 25% (CYP3A4), 19% (CYP2C18), and 14% (CYP3A5). CYP3A4 and CYP2C19 were highly expressed in the duodenum and ileum, but not in the colon and rectum. In the ileum, apical transporters such as P-gp, PEPT1, BCRP, MRP2, and ASBT were strongly expressed, and the expression levels of P-gp and ASBT in the ileum were higher than those in other regions. In the ileum, basolateral transporters such as OSTα, OSTβ, and MRP3 were strongly expressed. Furthermore, we identified specific markers for the duodenum, ileum, colon, and rectum by conducting comprehensive gene expression analysis. We succeeded in obtaining gene expression profiles of drug ADME-related genes in vivo human intestinal epithelial cells. We expect that this information would be useful for accurate prediction of the pharmacokinetics of oral drugs.
2021-04-30 | GSE156453 | GEO
Project description:Knowing the gene expression profiles of drug-metabolizing enzymes and transporters throughout gestation is important for understanding the mechanisms of pregnancy-induced changes in drug pharmacokinetics. In this study, we compared gene expression of drug-metabolizing enzymes and transporters in the maternal liver, kidney, small intestine, and placenta of pregnant mice throughout gestation by microarray analysis. Specifically, we investigated cytochrome P450 (Cyp), UDP-glucuronosyltranserase (Ugt), and sulfotransferase (Sult), as well as ATP-binding cassette (Abc) and solute carrier (Slc) transporters. We found that relatively few Ugt and Sult genes were impacted by pregnancy in maternal tissues and placenta. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 in the liver were down-regulated, with the greatest changes occurring on gestation days (gd) 15 and 19 compared to non-pregnant controls (gd 0). However, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. Cyp expression in mid-gestation placenta (gd 10 and 15) was generally greater than that in term placenta (gd 19). There were also notable changes in Abc and Slc transporters. Abcc3 in the liver was down-regulated by 60%, and Abcb1a, Abcc4, and Slco4c1 in the kidney were down-regulated by 30-60% on gd 15 and 19 versus gd 0. Abcc5 in the placenta was induced 3-fold on gd 10 versus gd 15 and 19, whereas Slc22a3 expression in the placenta on gd 10 was 90% lower than that on gd 15 and 19. Overall, this study demonstrates important gestational age-dependent expression of drug-metabolizing enzymes and transporter genes, which may have mechanistic relevance to human pregnancy. Ninety pregnant mice at gestational days 0, 7.5, 10, 15, and 19 (n = 5-6 per gestational age) were used for the maternal liver, kidney, small intestine and placenta. The placentas were collected on gestational days 10, 15, and 19.
2013-10-08 | E-GEOD-41438 | biostudies-arrayexpress
Project description:Knowing the gene expression profiles of drug-metabolizing enzymes and transporters throughout gestation is important for understanding the mechanisms of pregnancy-induced changes in drug pharmacokinetics. In this study, we compared gene expression of drug-metabolizing enzymes and transporters in the maternal liver, kidney, small intestine, and placenta of pregnant mice throughout gestation by microarray analysis. Specifically, we investigated cytochrome P450 (Cyp), UDP-glucuronosyltranserase (Ugt), and sulfotransferase (Sult), as well as ATP-binding cassette (Abc) and solute carrier (Slc) transporters. We found that relatively few Ugt and Sult genes were impacted by pregnancy in maternal tissues and placenta. Cyp1a2, most Cyp2 isoforms, Cyp3a11, and Cyp3a13 in the liver were down-regulated, with the greatest changes occurring on gestation days (gd) 15 and 19 compared to non-pregnant controls (gd 0). However, Cyp2d40, Cyp3a16, Cyp3a41a, Cyp3a41b, and Cyp3a44 in the liver were induced throughout pregnancy. Cyp expression in mid-gestation placenta (gd 10 and 15) was generally greater than that in term placenta (gd 19). There were also notable changes in Abc and Slc transporters. Abcc3 in the liver was down-regulated by 60%, and Abcb1a, Abcc4, and Slco4c1 in the kidney were down-regulated by 30-60% on gd 15 and 19 versus gd 0. Abcc5 in the placenta was induced 3-fold on gd 10 versus gd 15 and 19, whereas Slc22a3 expression in the placenta on gd 10 was 90% lower than that on gd 15 and 19. Overall, this study demonstrates important gestational age-dependent expression of drug-metabolizing enzymes and transporter genes, which may have mechanistic relevance to human pregnancy.
2013-10-08 | GSE41438 | GEO
Project description:Irinotecan (CPT-11) is now widely used as the first-line chemotherapy for mCRC. There were 4 key enzymes for CPT-11 metabolizing, CYP3A4, UDP-glucuronosyltransferase, carboxylesterase(CES), and ATP-binding cassette (ABC) transporters. Genetic variations of those enzymes may cause the heterogeneity in safety and efficacy of CPT-11. The aim of this study is to figure out the correlation between the genetic polymorphism and the drug response.
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Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp) genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S -transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification. We used microarrays to detail the global programme of gene expression in response to Nrf2 activation and identified distinct classes of up- and down-regulated genes. process. Gene expression in livers of Nrf2-null, WT, Keap1-KD, and Keap1-HKO mice was determined using Affymetrix Mouse 430.20 arrays by the KUMC Microarray Core Facility. Biological cRNA replicates (n=3) of each genotype were hybridized to an individual array.
2014-02-18 | E-GEOD-55001 | biostudies-arrayexpress
Project description:The intestine is an organ responsible for absorption and metabolism of orally administered drugs. It is necessary to examine the human intestinal expression profiles of the genes related to drug absorption, distribution, metabolism, and excretion (ADME), for accurate prediction of pharmacokinetics in the intestine. However, previous studies had issues such as the evaluation limited to specific molecules and regions, and relatively small sample sizes. In this study, to obtain more accurate expression profiles of mRNA and protein in various regions of human intestine, biopsy samples were collected from 38 patients with various regions, duodenum, jejunum, ileum, colon and rectum, and RNA-seq analysis and quantitative proteomics analysis were performed. We performed the expression analysis of drug-metabolizing enzymes (cytochromes P450 (CYP ) and non–CYP enzymes), apical and basolateral drug transporters, and nuclear receptors. Overall, mRNA expression levels of these ADME-related molecules were highly correlated with the protein expression levels. The characteristics of the expression of ADME-related genes in human small and large intestines differed significantly, such as higher or lower expression levels of CYP enzymes in the small or large intestines, respectively. Most CYPs were expressed dominantly in the small intestine. Non-CYPs were expressed in the large intestine, but their expression levels were lower than those in the small intestine. The expression levels of ADME-related genes differed even between the proximal and distal small intestine. The expression of transporters showed their highest abundance in the ileum. The data in the present study contributes to an improved understanding of intestinal ADME of drug candidates, and would be useful for drug discovery research.
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Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that induces a battery of cytoprotective genes in response to oxidative/electrophilic stress. Kelch-like ECH associating protein 1 (Keap1) sequesters Nrf2 in the cytosol. The purpose of this study was to investigate the role of Nrf2 in regulating the mRNA of genes encoding drug metabolizing enzymes and xenobiotic transporters. Microarray analysis was performed in livers of Nrf2-null, wild-type, Keap1-knockdown mice with increased Nrf2 activation, and Keap1-hepatocyte knockout mice with maximum Nrf2 activation. In general, Nrf2 did not have a marked effect on uptake transporters, but the mRNAs of organic anion transporting polypeptide 1a1, sodium taurocholate cotransporting polypeptide, and organic anion transporter 2 were decreased with Nrf2 activation. The effect of Nrf2 on cytochrome P450 (Cyp) genes was minimal, with only Cyp2a5, Cyp2c50, Cyp2c54, and Cyp2g1 increased, and Cyp2u1 decreased with enhanced Nrf2 activation. However, Nrf2 increased mRNA of many other phase-I enzymes, such as aldo-keto reductases, carbonyl reductases, and aldehyde dehydrogenase 1. Many genes involved in phase-II drug metabolism were induced by Nrf2, including glutathione S -transferases, UDP- glucuronosyltransferases, and UDP-glucuronic acid synthesis enzymes. Efflux transporters, such as multidrug resistance-associated proteins, breast cancer resistant protein, as well as ATP-binding cassette g5 and g8 were induced by Nrf2. In conclusion, Nrf2 markedly alters hepatic mRNA of a large number of drug metabolizing enzymes and xenobiotic transporters, and thus Nrf2 plays a central role in xenobiotic metabolism and detoxification. We used microarrays to detail the global programme of gene expression in response to Nrf2 activation and identified distinct classes of up- and down-regulated genes. process.
2014-02-18 | GSE55001 | GEO
Project description:Hepatocyte Nuclear Factors 4a and 1a (Hnf4a and Hnf1a) Regulate Kidney Developmental Expression of Drug-Metabolizing Enzymes and Drug Transporters
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Project description:We report label-free quantification of xenobiotic metabolizing enzymes (XME), transporters, redox enzymes, proteases and nucleases in 20 human liver microsomal samples. More than 3500 proteins were identified and quantified. These data can be used in physiologically based pharmacokinetic models to predict appropriate drug doses in children.
2021-09-09 | PXD020844 | Pride
Project description:We report label-free quantification of xenobiotic metabolizing enzymes (XME), transporters, redox enzymes, proteases and nucleases in 20 human liver microsomal samples. More than 3500 proteins were identified and quantified. These data can be used in physiologically based pharmacokinetic models to predict appropriate drug doses for a wide variety of drugs.
2021-09-08 | PXD020910 | Pride