Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism
Autor: | Xiao-bo Zhong, Shuang Wang, Christopher Wesselman, Ye Li, Steven N. Hart, Kaori Nakamoto |
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Rok vydání: | 2008 |
Předmět: |
Adult
Male Drug Adolescent media_common.quotation_subject Molecular Sequence Data Flavoprotein Biology Polymorphism Single Nucleotide Catalysis Cohort Studies chemistry.chemical_compound Cytochrome P-450 Enzyme System Biosynthesis Genetics Humans Amino Acid Sequence General Pharmacology Toxicology and Pharmaceutics Child Molecular Biology Genetics (clinical) media_common chemistry.chemical_classification Sequence Homology Amino Acid Infant Newborn Infant Cytochrome P450 Metabolism Middle Aged Molecular biology Enzyme Pharmaceutical Preparations chemistry Biochemistry Child Preschool Microsomes Liver biology.protein Molecular Medicine Female Pharmacogenetics Drug metabolism |
Zdroj: | Pharmacogenetics and Genomics. 18:11-24 |
ISSN: | 1744-6872 |
Popis: | Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes, which catalyze the biosynthesis of steroids, fatty acids, and bile acids, as well as metabolism of more than 80% of prescription drugs. Although mutations in POR have been identified in several disease states with disordered steroidogenesis, effects of polymorphisms on drug metabolism in the general population are unclear. In this report, we performed a comprehensive study to correlate POR polymorphisms with POR gene expression, POR activity, and P450-catalyzed drug metabolism.A set of human liver samples (n=99) were used in this study. POR polymorphisms were identified by sequencing the exons and surrounding introns of the POR gene and mRNA levels were quantified by branched DNA technology. POR activity was quantified by measuring cytochrome c reduction in liver microsomes and activities of 10 drug-metabolizing P450 enzymes were quantified by high performance liquid chromatography methods with drugs known to be specific for each enzyme.Of the 34 polymorphisms identified in this cohort, four polymorphisms changed an amino acid: K49N, L420M, A503V, and L577P. L577P likely resulted in an alpha helix change, possible disruption of the nicotinamide adenine dinucleotide phosphate interaction, and decreased POR activity (P=0.003) and several drug-metabolizing P450 activities. We also found an intronic polymorphisms rs41301427, which was associated with altered POR, but not P450 activities.Polymorphisms in the POR gene can affect POR and P450-catalyzed drug oxidation. These results suggest that POR has the potential to serve as a predictive biomarker for pharmacogenomic testing. |
Databáze: | OpenAIRE |
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