PHARMACOGENETICS OF PHASE II DRUG METABOLIZING ENZYMES

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Pharmacogenetics is the study of the role of inheritance in individual variation in drug response. Most pharmacogenetic variation that has been studied to this time involves individual variation in drug metabolism. Reactions involved in the metabolism of drugs are classified as either "phase I" or "phase II". Phase II drug metabolism includes conjugation reactions, and for over 20 years the Mayo pharmacogenetics research program has contributed to understanding of the biochemical, molecular and genomic basis for inherited variations in phase II pathways of drug metabolism. The present application proposes to build on that foundation to take advantage of the convergence of advances in molecular pharmacogenetics and human genomics to determine and make available to the biomedical research community information with regard to common, single nucleotide polymorphisms (SNPs) as well as insertion/deletion events within genes that encode proteins that catalyze phase II pathways of drug metabolism in humans -- with special emphasis on those enzymes that catalyze methyl and sulfate conjugation. However, the proposal goes beyond merely rapidly providing data on common sequence variations in genes for phase II drug-metabolizing enzymes to also include studies designed to determine the functional significance of inherited alterations in encoded amino acid sequence that result from these common genetic polymorphisms. Since functionally significant variations in amino acid sequence can potentially alter either the catalytic properties of an enzyme or, as has been found to be increasingly common, they can alter the level of enzyme protein, the proposed functional genomic studies will focus on these two possibilities. They will also include homology-based structural modeling for selected proteins in an attempt to test the hypothesis that it may be possible to predict the functional consequences of inherited alteration in encoded amino acid sequence for phase II enzymes. Therefore, this integrated approach will combine determinations of inherited nucleotide sequence variation, the functional consequences of gene sequence variation that alters encoded amino acids, homology-based structural modeling, and -- finally -- it will also include the evaluation of high throughput analytical techniques for SNP and insertion/deletion detection that could potentially be applied in a clinical research setting, thus making it possible to apply pharmacogenetic information to test medically relevant hypotheses with regard to individual variations in drug response. In summary, a comprehensive, integrated program of pharmacogenomic and pharmacogenetic studies of phase II drug-metabolizing enzymes, with special emphasis on methyltransferase and sulfotransferase enzymes, is proposed.