Single nucleotide polymorphisms in cytochrome P450 oxidoreductase influence drug metabolism

Abstract

Cytochrome P450 oxidoreductase (POR) is the only protein that donates electrons to all microsomal P450 enzymes, which metabolize more than 80% of prescription drugs. Our objective was to determine if polymorphisms in POR could affect gene expression and activity of POR, and/or P450‐catalyzed drug metabolism. POR polymorphisms were identified from non‐diseased human livers (n=99) by sequencing the POR gene and mRNA levels were quantified by the branched DNA method. POR activity was quantified by measuring cytochrome c reduction in liver microsomes and activities of ten drug‐metabolizing P450 enzymes were quantified by HPLC. Of the 34 identified polymorphisms, 9 were novel, 9 were in exons, and 4 changed an amino acid: K49N, L420M, A503V, and L577P. We report a novel exonic polymorphism, L577P (patent pending), which is associated with decreased POR (p=0.003) and several P450 activities. Our data suggest that [1] POR is functionally polymorphic in the general population and [2] has the potential to serve as a biomarker to optimize pharmacologic dosing strategies. This work was supported by NIH COBRE 5P20 RR021940 and Pharmaceutical Research and Manufacturers of America Foundation (PhRMA).