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| CYP2C19 | |
|---|---|
| Name | CYP2C19 |
| Ec number | 1.14.-.- |
| Family | Cytochrome P450 |
| Location | Chromosome 10q23.33 |
CYP2C19 CYP2C19 is a human cytochrome P450 enzyme involved in oxidative metabolism of numerous xenobiotics and endogenous substrates. Discovered through biochemical fractionation and molecular cloning efforts, it has been characterized by geneticists, pharmacologists, and clinicians for its role in variable drug response. Research on CYP2C19 intersects with work by investigators at institutions such as National Institutes of Health, Massachusetts General Hospital, University of Oxford, Stanford University School of Medicine, and pharmaceutical companies including Pfizer, Roche, and GlaxoSmithKline.
CYP2C19 is encoded on chromosome 10 and belongs to the CYP2C subfamily characterized by the heme-binding motif and canonical cytochrome P450 fold studied by groups including those at Harvard Medical School, Cambridge University, Max Planck Society, ETH Zurich, and Scripps Research. High-resolution structural models rely on homology to crystallized P450s from labs such as Stanford University and University of California, San Diego and have informed mutagenesis work reported by teams at University of Tokyo, Kyoto University, and Seoul National University Hospital. Genetic mapping and sequencing projects including the Human Genome Project, 1000 Genomes Project, and the Exome Aggregation Consortium have cataloged CYP2C19 variants, while bioinformatics resources at Ensembl, NCBI, and UCSC Genome Browser provide annotation used by consortia like the Pharmacogenomics Knowledgebase.
CYP2C19 catalyzes monooxygenation reactions converting substrates via NADPH-dependent electron transfer mediated by cytochrome P450 reductase in hepatic microsomes characterized in studies from Mayo Clinic, Cleveland Clinic, and University College London. Substrates include proton pump inhibitors studied in trials at Vanderbilt University Medical Center and antidepressants evaluated by researchers at Johns Hopkins University and Columbia University Irving Medical Center. CYP2C19 contributes to biotransformation of antiplatelet agents investigated in randomized trials at Brigham and Women's Hospital and University of Pennsylvania Health System, benzodiazepines examined in pharmacology labs at University of California, San Francisco, and endogenous steroids analyzed by teams at Karolinska Institutet and Institut Pasteur.
Common alleles such as *2, *3, *17 and others were first described by molecular genetics groups at University of Washington, University of Groningen, and McGill University. Functional classifications (poor, intermediate, extensive, ultrarapid metabolizers) derive from genotype-phenotype correlation studies from centers including Mayo Clinic Proceedings investigators, Duke University Medical Center pharmacogenetics programs, and the Clinical Pharmacogenetics Implementation Consortium working with collaborators at Food and Drug Administration and European Medicines Agency. Allelic nomenclature is curated by panels associated with PharmVar, and population-scale sequencing by 1000 Genomes Project and GenomeAsia 100K has refined allele catalogs used by genomic diagnostic labs such as Quest Diagnostics and LabCorp.
Clinical implications for drugs including clopidogrel, omeprazole, diazepam, and certain selective serotonin reuptake inhibitors were demonstrated in clinical trials at Cleveland Clinic Foundation, Massachusetts General Hospital, and Mount Sinai Health System. Guideline development has involved organizations such as Clinical Pharmacogenetics Implementation Consortium, European Society of Cardiology, American College of Cardiology, and regulatory review by the United States Food and Drug Administration. Pharmacokinetic modeling efforts integrating data from University of Washington and Pediatric Pharmacology Research Unit networks inform dosing recommendations used in hospital systems like Kaiser Permanente.
Therapeutic recommendations based on CYP2C19 genotype are incorporated into practice guidelines produced by groups including CPIC and specialty societies such as European Society of Cardiology and American Psychiatric Association. Implementation studies at health systems such as Vanderbilt University Medical Center and Geisinger Health System illustrate clinical decision support integration with electronic health records developed by vendors like Epic Systems and Cerner Corporation. Drug label changes influenced by genotype evidence have been processed through regulatory agencies including the FDA and European Medicines Agency, and pharmacoeconomic analyses by researchers at Johns Hopkins Bloomberg School of Public Health assess cost-effectiveness in health services studied at Agency for Healthcare Research and Quality.
Allele frequencies vary across populations documented by consortia including the 1000 Genomes Project, HapMap Project, and regional studies from institutions such as Peking University, All India Institute of Medical Sciences, University of Cape Town, and University of São Paulo. Frequencies of poor metabolizer alleles are higher in East Asian cohorts reported by Seoul National University and Fudan University investigators, while *17 is more prevalent in cohorts studied by researchers at University of Barcelona and University College Dublin. Epidemiological data informing public health policies have been reviewed by organizations like the World Health Organization and regional ministries of health.
Experimental approaches include recombinant expression systems developed at University of Geneva and Massachusetts Institute of Technology, transgenic and knockout mouse models produced by centers such as Jackson Laboratory and European Molecular Biology Laboratory, and in vitro systems using hepatocytes from biobanks like American Type Culture Collection and collaborations with Human BioMolecular Atlas Program. Ongoing translational research is supported by funding bodies including the National Institutes of Health, Wellcome Trust, and European Research Council, and reported in journals such as Nature Medicine, The Lancet, New England Journal of Medicine, and Clinical Pharmacology & Therapeutics.
Category:Cytochrome P450 enzymes