PHARMACOGENETICS OF PHASE II DRUG METABOLIZING ENZYMES

药物遗传学是研究遗传在药物反应中个体变异中的作用的学科。到目前为止所研究的大多数药物遗传变异涉及药物代谢的个体差异。参与药物新陈代谢的反应分为“第一阶段”或“第二阶段”。第二阶段药物代谢包括接合反应，20多年来，梅奥药物遗传学研究计划有助于了解药物代谢第二阶段途径遗传变异的生化、分子和基因组基础。本申请建议在此基础上利用分子药物遗传学和人类基因组学方面的进展的融合，确定并向生物医学研究界提供关于共同的单核苷酸多态(SNPs)以及编码催化人类药物代谢第二阶段途径的蛋白质的基因内的插入/缺失事件的信息--特别强调催化甲基和硫酸盐结合的那些酶。然而，该提案不仅仅是快速提供第二阶段药物代谢酶基因常见序列变异的数据，还包括旨在确定由这些常见遗传多态导致的编码氨基酸序列遗传变化的功能意义的研究。由于氨基酸序列在功能上的显著变化可能会改变酶的催化性质，或者正如越来越常见的那样，它们可以改变酶蛋白的水平，因此拟议的功能基因组研究将集中在这两种可能性上。他们还将包括对选定蛋白质进行基于同源性的结构建模，以试图测试这一假设，即可能预测II相酶编码氨基酸序列的遗传改变的功能后果。因此，这一综合方法将结合遗传核苷酸序列变异的测定、改变编码氨基酸的基因序列变异的功能后果、基于同源性的结构建模，以及--最后--它还将包括对SNP的高通量分析技术的评估，以及可能应用于临床研究环境的插入/缺失检测，从而使应用药物遗传学信息来测试与药物反应的个体变化有关的医学相关假说成为可能。综上所述，提出了一项全面的、综合的第二阶段药物代谢酶的药物基因组和药物遗传学研究计划，特别强调甲基转移酶和磺基转移酶。

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.