Human aromatase (CYP19) pharmacogenomics: Gene resequencing and functional genomics

Background/Aims CYP19 is a key enzyme in estrogen biosynthesis. CYP19 inhibitors are used to treat breast cancer. We set out to identify and characterize genetic polymorphisms in CYP19 as a step toward pharmacogenomic studies of aromatase inhibitors. Methods We resequenced the CYP19 5′‐untranslated exons PII and 1.3, as well as the 9 coding exons (exons 2 to 10), intron‐exon splice junctions and portions of the 3'‐untranslated region in 240 DNA samples from 4 ethnic groups. Results 28 polymorphisms were identified. Functional genomic studies were performed with the 4 nonsynonymous coding SNPs which altered the following amino acids: Trp39Arg, Thr201Met, Arg264Cys, and Met364Thr. The Cys264, Thr364 and the double variant Arg39,Cys264 allozymes showed significant decreases in levels of activity and enzyme protein after transient expression in COS‐1 cells. A 4‐fold increase in apparent K m was observed for Thr364 with androstenedione as substrate. None of the recombinant allozymes had significant changes in K i values for the aromatase inhibitors exemestane and letrozole. Conclusions Genetic variation in CYP19 might contribute to variation in the occurrence of estrogen‐dependent disease and/or response to aromatase inhibitors. Clinical Pharmacology & Therapeutics (2005) 77 , P22–P22; doi: 10.1016/j.clpt.2004.11.085