Effect of Cyp3a-cluster knockout on liver
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE103533 | GEO | 2018/11/15
REPOSITORIES: GEO
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Project description:Analysis of small intestine with or without Cytochrome P450 (Cyp) 3a-cluster. Cyp3a family is one of the most important enzymes for drug metabolism. These results suggest the biological effects of Cyp3a-knockout on small intestine.
2018-11-15 | GSE103534 | GEO
Project description:Many of the enzymes involved in xenobiotic metabolism are maintained at a low basal level and are only synthesized in response to activation of upstream sensor/effector proteins. This induction can have implications in a variety of contexts, particularly during the study of the pharmacokinetics, pharmacodynamics and drug-drug interaction profile of a candidate therapeutic compound. Previously, we combined in vivo SILAC material with a targeted high resolution single ion monitoring (tHR/SIM) LC-MS/MS approach for quantification of 197 peptide pairs, representing 51 drug metabolism enzymes (DME), in mouse liver. However, as important enzymes (for example, cytochromes P450 (Cyp) of the 1a and 2b subfamilies) are maintained at low or undetectable levels in the liver of unstimulated metabolically-labelled mice, quantification of these proteins was unreliable. In the present study, we induced DME expression in labelled mice through synchronous ligand-mediated activation of multiple upstream nuclear receptors, thereby enhancing signals for proteins including Cyps 1a, 2a, 2b, 2c and 3a. With this enhancement, 115 unique, lysine-containing, Cyp-derived peptides were detected in the liver of a single animal, as opposed to 56 in a pooled sample from three uninduced animals. A total of 386 peptide pairs were quantified by tHR/SIM, representing 68 Phase I, 30 Phase II and 8 control proteins. This method was employed to quantify changes in DME expression in the hepatic cytochrome P450 reductase null (HRN) mouse. We observed compensatory induction of several enzymes, including Cyps 2b10, 2c29, 2c37, 2c54, 2c55, 2e1, 3a11 and 3a13, carboxylesterase (Ces) 2a and glutathione S-transferases (Gst) m2 and m3, along with down-regulation of hydroxysteroid dehydrogenases (Hsd) 11b1 and 17b6. Using DME-enhanced in vivo SILAC material with tHR/SIM, therefore, permits the robust analysis of multiple DME of import to xenobiotic metabolism, with improved utility for the study of drug pharmacokinetics, pharmacodynamics, and of chemically-treated and genetically-modified mouse models.
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Project description:Endogenous gene expression profiling of Cyp3a-cluster knockout mice
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Project description:Purpose: To know the expression of all cytochrome P450 (CYP) enzymes and related drug metabolizing enzymes in pancreatic cancer models Methods: We obtained expression profiles of 8 commercially-available pancreatic cancer cell lines and one non-cancerous immortalized cell line by RNA-sequencing. The pancreatic cancer cells were compared among themselves and to the non-cancerous control cells. Results: We confirmed reports that CYP3A5 is highly overexpressed in pancreatic cancer models, and additionally report that known xenobiotic-metabolizing CYPs are lowly expressed in comparison.
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Project description:Paired RNA-Seq of 32 samples of chemo-naïve and post-chemotherapy PDAC tumors (HIPO_015) to define the molecular and cellular impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high resolution mapping of whole tissue sections identified GATA6 (Classical), KRT17 (Basal-like) and Cytochrome P450 3A (CYP3A) co-expressing cells that were preferentially enriched in post-CTX resected samples. The sequencing was done on HiSeq2000/HiSeq2500 using the Takara_SMARTer_Ultra_Low_Input_RNA_and_NEBNext_ChIP-Seq Kit.
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Project description:Protein adducts formed by drugs or their reactive metabolites are risk factors for adverse reactions, toxicity and inactivation of cytochrome P450 (CYP) enzymes. Characterization of drug-protein adducts is limited due to lack of methods capable of discovering the proteins and peptides adducted by reactive metabolites in complex matrices. The current study presents a proteomics workflow that achieves this task. This workflow combines data-dependent, and data independent acquisition (DDA and DIA) based LC-MS/MS and is sensitive enough to detect very low abundance adducts resulting from CYP mediated drug metabolism in human livers. Human liver microsomes (HLMs) or recombinant CYPs were incubated with raloxifene as a model compound. The resulting adducts were identified using this workflow. In HLMs, raloxifene adducts were detected in 78 proteins, including multiple adducts in CYP3A and CYP2C family enzymes. Experiments with recombinant CYP3A and CYP2C enzymes confirmed adduct formation in all CYPs tested, including CYPs not subject to time dependent inactivation (TDI) by raloxifene. These data suggest many adducts formed by reactive intermediates are benign. DIA analysis showed variable abundance of raloxifene adducts in many proteins between livers, but no concomitant decrease in abundance of unadducted peptides. The current study sets a new standard for adduct detection in complex samples, offering valuable insights into the human adductome resulting from exposure to reactive metabolites. The developed methodology forms a foundation for mechanistic studies to identify, quantify and differentiate between adducts that result in adverse drug reactions and drug-drug interactions and adducts that do not.
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Project description:The soil nematode Caenorhabditis elegans is one of the simplest animals having the status of a laboratory model. Its genome contains 80 cytochrome P450 genes (CYP). In order to study CYP gene expression in C. elegans mixed stages and synchronized hermaphrodites were exposed to 18 known xenobiotic cytochrome P450 inducers. Messenger RNA expression was detected by DNA arrays and semiquantitative RT-PCR. Using subfamily-specific primers, a pooled set of exon-rich CYP fragments could be amplified. In this way it was possible to systematically check the influence of different inducers on CYP expression at the same time. The well-known CYP1A inducers beta-naphthoflavone, PCB52, and lansoprazol were the most active and in particular they strongly induced almost all CYP35 isoforms. A few number of further CYP forms were found to be inducible by other xenobiotics like phenobarbital, atrazine, and clofibrate. In addition, a transgenic C. elegans line expressing GFP under control of the CYP35A2 promoter showed a strong induction of the fusion by beta-naphthoflavone in the intestine. Copyright 2001 Academic Press. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Computed
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Project description:The HIF (hypoxia-inducible factor) transcription factor is the master regulator of the metazoan response to chronic hypoxia. In addition to promoting adaptations to low oxygen, HIF drives cytoprotective mechanisms in response to stresses and modulates neural circuit function. How most HIF targets act in the control of the diverse aspects of HIF-regulated biology remains unknown. We discovered that a HIF target, the C. elegans gene cyp-36A1, is required for numerous HIF-dependent processes, including modulation of gene expression, stress resistance, and behavior. cyp-36A1 encodes a cytochrome P450 enzyme that we show controls expression of more than a third of HIF-induced genes. CYP-36A1 acts cell non-autonomously by regulating the activity of the nuclear hormone receptor NHR-46, suggesting that CYP-36A1 functions as a biosynthetic enzyme for a hormone ligand of this receptor. We propose that regulation of HIF effectors through activation of cytochrome P450 enzyme/nuclear receptor signaling pathways could similarly occur in humans.
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Project description:Background and Aim: Liver cirrhosis is associated with decreased hepatic cytochrome P4503A (CYP3A) activity but the pathogenesis of this phenomenon is not well elucidated. In this study, we examined if certain microRNAs (miRNA) are associated with decreased hepatic CYP3A activity in cirrhosis. Hepatic CYP3A activity and miRNA microarray expression profiles were measured in cirrhotic (n=22) and normal (n=12) liver tissue. Hepatic CYP3A activity was measured via midazolam hydroxylation in human liver microsomes. Additionally, hepatic CYP3A4 protein concentration and the expression of CYP3A4 mRNA were measured. Analyses were conducted to identify miRNAs which were differentially expressed between two groups but also were significantly associated with lower hepatic CYP3A activity.
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