Aspirin, UGT1A6 Genotype, and Colon Gene Expression

描述（由申请人提供）：结肠直肠癌被认为是由于 这是一系列分子变化的结果 细胞转化为结直肠癌，中间为腺瘤性息肉。 在这个过程中的一步。降低这种癌症死亡率的一种方法是 使用口服药物预防大肠肿瘤的发展。 经常使用阿司匹林和其他非甾体抗炎药（NSAID） 降低结肠腺瘤和癌的发病率， 50%。主要参与代谢阿司匹林的酶是 UDP-葡萄糖醛酸转移酶（UGT）。UGT 1A 6是一种多态性UGT及其变体 等位基因代谢阿司匹林的效率较低。我们发现非甾体抗炎药使用者， 尤其是阿司匹林使用者， 在UGT 1A 6杂合和纯合变异个体中， 纯合野生型。阿司匹林及其代谢产物水杨酸可以抑制 通过抑制环加氧酶（前列腺素的催化剂 合成），促进细胞凋亡，和其他尚未确定的途径。 本项目的目的是确定UGT 1A 6基因型对 阿司匹林代谢和阿司匹林诱导的结肠基因表达变化 以及凋亡的蛋白标志物（Bax和Bcl-2）。我们建议研究：1） 380名健康人阿司匹林代谢产物的尿排泄 横断面研究中不同的UGT 1A 6基因型和2）结肠中的变化 在一个随机的， 一项安慰剂对照试验，40例纯合子野生型 或UGT 1A 6的纯合变体。我们假设在慢代谢者中， 葡萄糖醛酸化代谢物的比例较小， 阿司匹林剂量的一部分在特定时间内排出。改变 在结肠中的基因表达将使用cDNA微阵列分析来确定， B型结肠和直肠的活检RNA以及Bax和Bcl-2的表达。 通过免疫组织化学测量结肠隐窝。我们假设 例如生长促进基因的表达将减少并发生凋亡 在服用阿司匹林的过程中，基因的表达增加，这种减少可能在服用阿司匹林的人中更强。 慢代谢者比快代谢者多。该项目还将使 确定其他基因的表达受阿司匹林的影响 补充。最终，从该项目中获得的信息将 可用于开发特异性靶向通路的化学预防药物， 与结肠肿瘤有关通过靶向相关通路， 可以避免使用NSAID或特异性考克斯-2抑制剂引起的不良反应。

DESCRIPTION (provided by applicant): Colorectal cancers are thought to arise as the result of a series of molecular changes that transform normal epithelial cells into a colorectal carcinoma, with an adenomatous polyp as an intermediate step in this process. One way to reduce mortality from this cancer involves the use of oral agents that prevent neoplasms from developing in the large bowel. Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) reduces the incidence of colon adenomas as well as carcinomas by approximately 50 percent. Enzymes prominently involved in metabolizing aspirin are UDP-glucuronosyltransferases (UGT). UGT1A6 is a polymorphic UGT and its variant alleles metabolize aspirin less efficiently. We showed that in NSAIDs users, and aspirin users in particular, the risk for colon neoplasia is reduced only in individuals who are UGT1A6 heterozygous and homozygous variant, but not homozygous wild-type. Aspirin and its metabolite, salicylic acid, can inhibit growth through the inhibition of cyclooxygenases (catalysts of prostaglandin synthesis), the promotion of apoptosis, and other as yet unidentified pathways. The goal of this project is to determine the effect of UGT1A6 genotype on aspirin metabolism and on aspirin-induced changes in colonic gene expression and protein markers of apoptosis (Bax and Bcl-2). We propose to study: 1) urinary excretion of aspirin metabolites in 380 healthy individuals with different UGT1A6 genotypes in a cross-sectional study and 2) changes in colon gene expression induced by aspirin supplementation in a randomized, placebo-controlled trial of 40 individuals who are either homozygous wild-type or homozygous variant for UGT1A6. We hypothesize that in slow metabolizers the proportion of glucuronidated metabolites is smaller and that a smaller proportion of the aspirin dose is excreted within a specific time. Alterations in colonic gene expression will be determined using cDNA microarray analysis of biopsy RNA from the sigmoid colon and rectum and Bax and Bcl-2 expression in the colonic crypts will be measured by immunohistochemistry. We hypothesize that expression of e.g. growth-promoting genes will be reduced and apoptotic genes increased during aspirin use and that this reduction may be stronger in slow metabolizers than fast metabolizers. This project will also allow the identification of other genes whose expression is affected by aspirin supplementation. Ultimately, information obtained from this project will be useful in developing chemopreventive drugs that specifically target pathways involved in colon neoplasia. By targeting relevant pathways, side effects caused by the use of NSAIDs or specific Cox-2 inhibitors may be avoided.