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Human aromatase (CYP19) pharmacogenomics: Gene resequencing and functional genomics
Author(s) -
Ma C.,
Adjei A.,
Salavaggione O.,
Wang L.,
Eckloff B.,
Wieben E.,
Adjei A.,
Weinshilboum R.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.085
Subject(s) - aromatase , nonsynonymous substitution , pharmacogenomics , exon , biology , genetics , single nucleotide polymorphism , gene , exemestane , intron , genotype , genome , breast cancer , cancer
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