| Effects of genetic variants of human P450 oxidoreductase on catalysis by CYP2D6 in vitro. | |
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MedLine Citation:
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PMID: 20940534 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVES: Cytochrome P450 (P450) oxidoreductase (POR) donates electrons to all microsomal cytochrome P450s, including drug-metabolizing and steroidogenic enzymes. Severe POR mutations cause skeletal malformations and disordered steroidogenesis. The POR polymorphism A503V is found on approximately 28% of human alleles and decreases activities of CYP3A4 and steroidogenic CYP17, but not the activities of steroidogenic CYP21 or drug-metabolizing CYP1A2 and CYP2C19. CYP2D6 metabolizes about 25% of clinically used drugs; we assessed the capacity of POR variants to support the activities of human CYP2D6. METHODS: N-27 forms of wildtype (WT), Q153R, A287P, R457H and A503V POR, and WT CYP2D6 were expressed in Escherichia coli. POR proteins in bacterial membranes were reconstituted with purified CYP2D6. Support of CYP2D6 was measured by metabolism of EOMCC (2H-1-benzopyran-3-carbonitrile,7-(ethoxy-methoxy)-2-oxo-(9Cl)), dextromethorphan and bufuralol. Michaelis constant (K(m)) and maximum velocity (V(max)) were determined in three triplicate experiments for each reaction; catalytic efficiency is expressed as V(max)/K(m). RESULTS: Compared with WT POR, disease-causing POR mutants A287P and R457H supported no detectable CYP2D6 activity with EOMCC, but A287P supported approximately 25% activity with dextromethorphan and bufuralol. Q153R had increased function with CYP2D6 (128% with EOMCC, 198% with dextromethorphan, 153% with bufuralol). A503V supported decreased CYP2D6 activity: 85% with EOMCC, 62% with dextromethorphan and 53% with bufuralol. CONCLUSION: POR variants have different effects depending on the substrate metabolized. Disease-causing POR mutations R457H and A287P had poor activities, suggesting that diminished drug metabolism should be considered in affected patients. The common A503V polymorphism impaired CYP2D6 activities with two commonly used drugs by 40-50%, potentially explaining some genetic variation in drug metabolism. |
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Authors:
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Duanpen Sandee; Kari Morrissey; Vishal Agrawal; Harrison K Tam; Melissa A Kramer; Timothy S Tracy; Kathleen M Giacomini; Walter L Miller |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Pharmacogenetics and genomics Volume: 20 ISSN: 1744-6880 ISO Abbreviation: Pharmacogenet. Genomics Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-13 Completed Date: 2011-02-09 Revised Date: 2013-04-19 |
Medline Journal Info:
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Nlm Unique ID: 101231005 Medline TA: Pharmacogenet Genomics Country: United States |
Other Details:
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Languages: eng Pagination: 677-86 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, University of California, San Francisco, California 94143-0978, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Benzopyrans
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metabolism Catalysis Cytochrome P-450 CYP2D6 / genetics, metabolism* Dextromethorphan / pharmacology Ethanolamines / pharmacology Genetic Variation* Humans Metabolic Detoxication, Drug / genetics Mutation NADPH-Ferrihemoprotein Reductase / genetics*, metabolism Oxidoreductases / genetics Polymorphism, Genetic |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM069753/GM/NIGMS NIH HHS; R01 GM073020/GM/NIGMS NIH HHS; R01 GM073020/GM/NIGMS NIH HHS; R01 GM073020-07/GM/NIGMS NIH HHS; R01 GM073020-08/GM/NIGMS NIH HHS; U01 GM061390/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzopyrans; 0/Ethanolamines; 125-71-3/Dextromethorphan; 891H89GFT4/bufuralol; EC 1.-/Oxidoreductases; EC 1.14.14.1/Cytochrome P-450 CYP2D6; EC 1.6.2.4/NADPH-Ferrihemoprotein Reductase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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