Pharmacogenetics of Phase II Drug Metabolizing Enzymes

DESCRIPTION (provided by applicant): This proposal represents a request for continuation of the Mayo Clinic Pharmacogenetics Research Network (PGRN) Research Program "Pharmacogenetics of Phase II Drug Metabolizing Enzymes". The Mayo PGRN is an integrated, multidisciplinary, multi-institutional research effort that is itself integrated within the overall NIH-sponsored multi-institution PGRN. The Mayo PGRN is based on a decades-long focus at Mayo on studies of the pharmacogenetics and pharmacogenomics of phase II (conjugating) drug-metabolizing enzymes. Those same enzymes also catalyze the conjugation of hormones such as estrogens and of monoamine neurotransmitters. The Mayo PGRN has utilized a genotype-to-phenotype research strategy that begins by re-sequencing genes which encode phase II enzymes, followed by characterization of the functional effects of genetic polymorphisms present in these genes -- with a special emphasis on mechanisms by which those polymorphisms influence function. That approach will be continued and expanded during the next funding period -- with a continued emphasis on providing genetic polymorphism, functional genomic and mechanistic data on phase II enzymes to the pharmacogenetic and pharmacogenomic research community - but also extending this research to include studies of the pharmacogenomics of the aromatase inhibitor anastrozole and the selective serotonin reuptake inhibitor (SSRI) escitalopram. Both of these clinical pharmacogenomic studies are based directly on the long history of Mayo PGRN pharmacogenomic studies of the role of phase II enzymes in the conjugation of estrogens, which are synthesized by aromatase, and the conjugation of monoamine neurotransmitters, whose function is altered by SSRIs such as escitalopram. All pharmacogenomic information obtained as a result of the research conducted by the Mayo PGRN will be rapidly deposited in the NIH-sponsored Pharm