Pharmacogenetics of Sulfate Conjugation

硫酸盐结合的药物遗传学

• 批准号: 6997801
• 负责人: VIRGIL CRAIG JORDAN
• 金额: $ 28.71万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-10 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6997801
• 关键词: African American; biotransformation; breast neoplasms; cancer risk; caucasian American; chemical conjugate; chemical kinetics; clinical research; estrogens; gene expression; genetic polymorphism; genetic susceptibility; hormone regulation /control mechanism; human genetic material tag; human subject; intermolecular interaction; neoplasm /cancer genetics; nucleic acid sequence; pharmacogenetics; protein isoforms; protein metabolism; protein structure function; racial /ethnic difference; sulfates; sulfotransferase; tissue /cell culture

DESCRIPTION (provided by applicant): Sulfate conjugation reactions are critical in the biotransformation of steroid hormones, neurotransmitters and several drugs. Sulfation reactions are catalyzed by cytosolic sulfotransferases (SULTs). SULT1 Al is a SULT isoform that catalyzes the conjugation of endogenous and exogenous estrogens as well drugs such as acetaminophen, minoxidil and 4-hydroxytamoxifen. SULTI El is a distinct SULT isoform that also sulfates estrogens. We have recently identified three common SULT1A1 alleles with different frequencies in Caucasian and African American populations. One of those alleles, SULTIA1 *2 was associated with significantly lower SULT1A1 activity in human tissues. The other allele, SULT1A1*3, is frequent in the African American population (23 percent) but not in Caucasians (1 percent). Biochemical analysis of the recombinant SULT1A1 *3 allozyme indicated that it had a ten-fold greater affinity for the sulfation cosubstrate, but the functional significance of this allele in human tissue has not yet been evaluated. This proposal seeks to examine the functional and clinical significance of those SULT1A1 polymorphisms, particularly in the context of SULT1 El redundancy. Purified recombinant SULT1 Al allozymes will be biochemically characterized with estrogen and antiestrogen substrates and compared with the biochemistry of another SULT isoform, SULT1 El. The association between the SULT1A1 *3 allele and the level of SULT1A1 activity and immunoreactive protein will be examined in platelets from African American individuals to determine genotype/phenotype correlation. Preliminary data suggested that the SULT1 Al *2 protein and/or mRNA was less stable than the SULT1 Al *1 enzyme. Therefore, the kinetics of allele-dependent SULT1 Al protein and mRNA synthesis and degradation will be assessed. Proliferative and transcriptional response to 17beta-estradiol, 2-methoxyestradiol and 4-hydroxytamoxifen will be studied and compared in MCF-7 cells stably expressing SULT1 El or SULT1A1 allozymes. Finally, the association between SULT1A1 alleles and specific breast cancer characteristics will be examined in a cohort of 600 Caucasian and African American women with breast cancer. These results will increase our understanding of the contribution of SULT1A1 pharmacogenetics to individual variation in response to estrogens and an important antiestrogen.

描述（申请人提供）：硫酸盐共轭反应至关重要 在类固醇激素，神经递质和几种类固醇激素的生物转化中 毒品。硫化反应是由胞质磺胺转移酶催化的 （Sults）。 Sult1 Al是一种苏格尔的同工型，它催化了结合 内源性和外源性雌激素以及对乙酰氨基酚等药物， 米诺地尔和4-羟基莫昔芬。 Sulti El是一种独特的苏特同工型 硫酸盐雌激素。我们最近确定了三个常见的sult1a1等位基因 在白种人和非裔美国人人口中有不同的频率。一 在这些等位基因中，Sultia1 *2与Sult1a1显着较低有关 人体组织的活性。另一个等位基因sult1a1*3在 非裔美国人人口（23％），但在高加索人（1％）中没有。 重组Sult1A1 *3同种酶的生化分析表明它 对硫酸化木质岩具有十倍的亲和力，但 该等位基因在人体组织中的功能意义尚未 评估。 该建议旨在检查 那些Sult1a1多态性，特别是在Sult1的背景下 冗余。纯化的重组Sult1 Al同种酶将是生化的 以雌激素和抗雌激素底物为特征，并与 另一种苏氏同工型的生物化学，Sult1 El。与 Sult1a1 *3等位基因以及Sult1a1活性和免疫反应性蛋白的水平 将在非裔美国人的血小板中检查以确定 基因型/表型相关。初步数据表明sult1 al *2 蛋白质和/或mRNA不如SULT1 AL *1酶稳定。因此， 等位基因依赖性Sult1 Al蛋白和mRNA合成的动力学以及 降解将被评估。对 将研究17beta-雌二醇，2-甲氧基丙二醇和4-羟基氧莫昔芬，并研究 在MCF-7细胞中比较稳定表达SULT1 EL或SULT1A1同种酶。 最后，Sult1a1等位基因与特定乳腺癌之间的关联 将在600名高加索人和非洲人的队列中检查特征 美国乳腺癌女性。这些结果将增加我们的 了解Sult1A1药物遗传学对个体的贡献 响应雌激素和重要的抗雌激素的变化。