Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism

Pharmacogenetics and Genomics
Steven N HartXiao-bo Zhong

Abstract

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, possi...Continue Reading

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Related Concepts

Catalysis
Cytochrome P-450 Oxygenase
Pharmaceutical Preparations
Microsomes, Liver
Incidence Studies
Homologous Sequences, Amino Acid
Single Nucleotide Polymorphism

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