| A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. | |
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MedLine Citation:
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PMID: 16413245 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND OBJECTIVE: Many drugs, including proton pump inhibitors and certain antidepressants, are metabolized by the polymorphic cytochrome P450 (CYP) 2C19 enzyme. A significant portion of extensive metabolizers do not reach appropriate drug levels, and our objective was to investigate any genetic background. METHODS: The 5'-flanking region of the CYP2C19 gene from subjects with rapid omeprazole metabolism was sequenced, and CYP2C19 phenotype-genotype associations were analyzed in Swedish (n = 107) and Ethiopian (n = 126) extensive metabolizers. The relationship of the metabolic ratio of omeprazole (omeprazole/5-hydroxyomeprazole in plasma 3 hours after drug intake) with the area under the plasma concentration-time curve was used for prediction studies. Electrophoretic mobility shift assays were conducted by use of human nuclear protein extracts. Hepatic reporter vector transfections were carried out in CD1 mice. RESULTS: We identified a novel allele (CYP2C19*17) carrying -806C>T and -3402C>T, with a frequency of 18% in both Swedes and Ethiopians and 4% in Chinese subjects. In Swedes the metabolic ratio of omeprazole was higher in subjects homozygous for CYP2C19*1 (median, 0.50 [interquartile range, 0.37-0.73]) than in those homozygous for CYP2C19*17 (median, 0.25 [interquartile range, 0.15-0.33]) (P = .010). In Ethiopians a similar difference in the S/R-mephenytoin ratio was observed between individuals homozygous for CYP2C19*1 (median, 0.20 [interquartile range, 0.12-0.37]) and those homozygous for CYP2C19*17 (median, 0.05 [interquartile range, 0.03-0.06]) (P = .013). Electrophoretic mobility shift assays showed specific binding of human hepatic nuclear proteins to an element carrying -806T but not -806C. Reporter vector experiments showed an increased transcriptional activity of the CYP2C19*17 allele in vivo in mice. Predictions revealed that CYP2C19*17 homozygotes would attain 35% to 40% lower omeprazole area under the plasma concentration-time curve values than subjects homozygous for CYP2C19*1 taking standard doses of omeprazole. CONCLUSION: CYP2C19*17 is likely to cause therapeutic failures in drug treatment with, for example, proton pump inhibitors and antidepressants. |
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Authors:
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Sarah C Sim; Carl Risinger; Marja-Liisa Dahl; Eleni Aklillu; Magnus Christensen; Leif Bertilsson; Magnus Ingelman-Sundberg |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Clinical pharmacology and therapeutics Volume: 79 ISSN: 0009-9236 ISO Abbreviation: Clin. Pharmacol. Ther. Publication Date: 2006 Jan |
Date Detail:
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Created Date: 2006-01-17 Completed Date: 2006-02-08 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 0372741 Medline TA: Clin Pharmacol Ther Country: United States |
Other Details:
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Languages: eng Pagination: 103-13 Citation Subset: AIM; IM |
Affiliation:
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Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm. Sarah.Sim@ki.se |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anticonvulsants / pharmacokinetics Antidepressive Agents / pharmacokinetics*, therapeutic use Aryl Hydrocarbon Hydroxylases / genetics* China / epidemiology Electrophoretic Mobility Shift Assay Enzyme Inhibitors / pharmacokinetics*, therapeutic use Ethiopia / epidemiology Gene Frequency Genes, Reporter / genetics Genetic Variation Genotype Humans Male Mephenytoin / pharmacokinetics Mice Mixed Function Oxygenases / genetics* Mutation Omeprazole / pharmacokinetics, therapeutic use Phenotype Plasmids / genetics Proton Pumps / antagonists & inhibitors* Reverse Transcriptase Polymerase Chain Reaction Sweden / epidemiology Transfection |
| Grant Support | |
ID/Acronym/Agency:
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1-R01 GM60548/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anticonvulsants; 0/Antidepressive Agents; 0/Enzyme Inhibitors; 0/Proton Pumps; 50-12-4/Mephenytoin; 73590-58-6/Omeprazole; EC 1.-/Mixed Function Oxygenases; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C19 protein, human |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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