Pharmacogenetics of Sulfate Conjugation

描述（由申请方提供）：硫酸盐结合反应至关重要 在类固醇激素、神经递质和一些 毒品硫酸化反应是由胞质磺基转移酶催化的 （SULT）。SULT 1 A1是催化SULT 1 A1和SULT 2的缀合的SULT同种型。 内源性和外源性雌激素以及药物如对乙酰氨基酚， 米诺地尔和4-羟基他莫昔芬。SULTIE1是一种独特的SULT同种型， 硫酸盐雌激素。我们最近发现了三种常见的SULT1A1等位基因 在高加索人和非裔美国人中的频率不同。一 在这些等位基因中，SULT1A1 * 2与显著较低的SULT1A1 人体组织中的活性。另一个等位基因SULT1A1 * 3在正常人中很常见。 非裔美国人（23%），但不是高加索人（1%）。 对重组SULT 1A1 * 3等位酶的生化分析表明， 对硫酸化共底物的亲和力高出10倍，但 该等位基因在人体组织中的功能意义尚未被 评估。 本建议旨在研究的功能和临床意义， 这些SULT1A1多态性，特别是在SULT1E1的情况下， 冗余纯化的重组SULT 1 Al等位酶将被生物化学纯化。 以雌激素和抗雌激素底物为特征，并与 另一种SULT同种型SULT 1 El的生物化学。之间的关联 SULT1A1 * 3等位基因与SULT1A1活性和免疫反应蛋白水平 将在非洲裔美国人的血小板中进行检查，以确定 基因型/表型相关初步数据表明，SULT 1 Al * 2 蛋白质和/或mRNA的稳定性低于SULT 1 A1 * 1酶。因此 等位基因依赖性SULT 1 A1蛋白和mRNA合成的动力学， 将评估退化。转录和转录反应， 将研究17 β-雌二醇、2-甲氧基雌二醇和4-羟基他莫昔芬， 在稳定表达SULT1E1或SULT1A1等位酶的MCF-7细胞中比较。 最后，SULT1A1等位基因与特定乳腺癌之间的关联 将在600名白人和非洲人的队列中检查这些特征。 美国女性乳腺癌患者这些成果将提高我们的 了解SULT1A1药物遗传学对个体的贡献 对雌激素和一种重要的抗雌激素反应的变化。

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.