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Novel in vivo regulatory mechanisms of human CYP3A4

人CYP3A4的新型体内调节机制

基本信息

批准号：
8656023
负责人：
Romi Ghose
金额：
$ 24.1万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8656023
关键词：
3&apos Untranslated Regions Antibodies Binding Binding Sites Bioinformatics Biological Assay CYP3A4 gene Cardiovascular Diseases Cells Chemicals Chromatin Communicable Diseases Complex Cytochrome P450 Cytochrome P450 3A4 DNA DNase-I Footprinting Development Diabetes Mellitus Disease Down-Regulation Drug Interactions Endotoxins Enhancers Environment Enzymes Epigenetic Process Future Gene Expression General Transcription Factors Genome Goals High-Throughput Nucleotide Sequencing Human Image Immunoprecipitation In Vitro Individual Infection Inflammation Mediators Lead Ligands Lipopolysaccharides Liver Liver diseases Luciferases Malignant Neoplasms Maps Measures Mediating Messenger RNA MicroRNAs Microarray Analysis Modification Molecular Mus Nuclear Orphan Receptor Nuclear Receptors Patients Pharmaceutical Preparations Plasmids Post-Transcriptional Regulation Proteins RNA RNA-Protein Interaction Reaction Regulation Regulatory Element Rifampin Risk Role Safety Site Techniques base chromatin immunoprecipitation chromatin modification crosslink cytokine deep sequencing drug metabolism gel mobility shift assay genome-wide hepatocyte nuclear factor improved in vivo inflammatory marker mRNA Expression mutant novel pregnane X receptor prevent promoter protein expression public health relevance research study transcription factor

项目摘要

ABSTRACT. Cytochrome P450 (CYP) 3A4 is the most abundant CYP enzyme in the human liver, and it metabolizes ~60% of known drugs. CYP3A4-mediated drug metabolism is impaired in patients with infections, diabetes, cancer, cardiovascular diseases, liver disorders and many other diseases. Disruptions in drug metabolism in diseases are associated with induction of inflammatory markers and reductions in expression of CYP enzymes. Thus, in most patients, medications are exposed to a micro-environment where inflammatory mediators are activated. This increases the risks of drug-drug interactions and adverse drug reactions in these patients. The objective of this exploratory proposal is to perform genome-wide mapping and bioinformatics analysis to identify key regulators involved in down-regulation of human CYP3A4 enzymes in vivo. CYP3A4 gene expression is regulated by basal transcription factors as well as nuclear receptors (NRs). In vitro studies have shown that CYP3A4 expression is also regulated by microRNAs (miRNAs). Thus, down-regulation of CYP3A4 enzymes may be a cumulative effect of transcriptional and post-transcriptional modifications by transcription factors, NRs and/or miRNAs. Our central hypothesis is that down-regulation of CYP3A4 expression is controlled by transcription factor/NR-associated epigenetic modifications at the target chromatin as well as by changes in miRNA binding to CYP3A4 mRNA. The first aim of this proposal will examine the hypothesis that down- regulation of CYP3A4 gene is controlled by transcription factor/NR-associated epigenetic modifications at the target chromatin. The second aim will determine the role of miRNAs in down-regulation of CYP3A4 enzymes in vivo. CYP3A4 expression can be activated by diverse chemicals which induce NRs, including pregnane X receptor (PXR). On the other hand, CYP3A4 can be down-regulated by inflammatory mediators including cytokines and the bacterial endotoxin, lipopolysaccharide (LPS) which are associated with diseases. To identify the key regulators involved in alteration of CYP3A4 enzymes, our strategy is to utilize a combined approach of CYP3A4 induction by PXR ligand (e.g. PCN) and CYP3A4 down-regulation by LPS. The proposed studies using genome-based approaches can unravel novel regulatory elements which contribute to down-regulation of human CYP3A4 enzymes in vivo. These regulators can then be targeted to prevent undesirable effects of drugs due to changes in CYP3A4-mediated drug metabolism. Ultimately, this can lead to the development of new strategies to improve the safety of medications in individual patients.

摘要。