PPII Abstract, 2005

Pharmacogenetics of Phase II Drug Metabolizing Enzymes

Goals

This project represents a 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 metabolism of hormones such as estrogens and of monoamine neurotransmitters.

Progress

The sequences of a large number of genes encoding "phase II" enzymes that catalyze the conjugation of drugs, neurotransmitters and hormones were determined during the initial funding period for this project. Functional genomic studies of nonsynonymous coding single nucleotide polymorphism (cSNPs) were performed for many of these genes, including TPMT, COMT, ASMT (CYT19), PNMT, SULT1A3, SULT1E1, SULT2A1, PAPSS1, PAPSS2, MTHFR and CYP19 (aromatase). One key observation made was that the most common mechanism by which nonsynonymous cSNPs alter protein function involves a decrease in protein quantity - most often as a result of accelerated proteasome-dependent degradation. The Mayo PGRN also reported that the clinically important TPMT*3A variant allele undergoes aggresome formation as a mechanism by which function is altered - a first in pharmacogenetics. In addition to gene resequencing and functional genomic studies, the Mayo PGRN also "translated" its findings to apply them to studies of the drug therapy of inflammatory bowel disease and childhood leukemia as well as the pathophysiology of breast cancer.

Experimental Plans

The Mayo PGRN - as described above - has most often utilized a genotype-to-phenotype research strategy that begins by resequencing 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 line of 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 PharmGKB Knowledge Base.