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).
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