UDP-GLUCURONYLTRANSFERASES

UDP-葡萄糖醛酸转移酶

• 批准号: 3273718
• 负责人: THOMAS R TEPHLY
• 金额: $ 19.36万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3273718
• 关键词: biotransformation; drug metabolism; estrogens; glucuronides; glucuronosyltransferase; hormone regulation /control mechanism; laboratory rabbit; laboratory rat; microsomes; morphine; nitrophenol; uridine diphosphate

Glucuronide conjugation is a major route of drug metabolism and provides living organisms with a way to eliminate lipid-soluble chemicals to which they are exposed. Hepatic microsomal UDP-glucuronyltransferases (UDPGTs) catalyze the formation of glucuronides. Our laboratory has isolated a number of these proteins which are important in the conjugation of xenobiotics and endogenous substances. Determination of hepatic lobular localization and distribution of p-nitrophenol UDP-glucuronyltransferase (PNP-UDPGT), 17Beta-OH steroid UDPGT and 3Alpha-OH steroid UDPGT by immunohistochemical analyses is planned. Using specific antibodies, studies will demonstrate the changes in distribution produced by various agents such as 3-methylcholanthrene. In addition, liver, gastrointestinal tract, lung and kidney will be studied from Wistar rats possessing high levels of 3Alpha-OH steroid UDPGT (HA) and low levels of 3Alpha-OH steroid UDPGT (LA). These studies will allow for an understanding of the role of cellular heterogeneity in glucuronidation. Experiments will reveal N-terminal amino acid sequences of PNP-UDPGT, 17Beta-OH steroid UDPGT and 3Alpha-OH steroid UDPGT. In addition, the genetic regulation of expression of these transferases in untreated rat livers and in livers of rats treated with 3-methylcholanthrene will be studied. The mechanism of genetic variance for 3Alpha-OH steroid UDPGT will be studied in HA and LA Wistar rats. Purification of morphine and digitoxigenin monodigitoxoside UDPGTs will be performed and, then, these enzymes will be studied further as described for other UDPGTs. Purification and characterization of human liver UDPGTs will be performed. Experiments on phospholipid requirements, N-terminal amino acid sequences and the genetic regulation of expression of human liver UDPGTs are planned. Finally, the role of cellular heterogeneity in human tissues will be explored using immunohistochemical methods. Thus, how and where glucuronidation occurs can be probed and understood.

葡萄糖醛酸结合是药物代谢的主要途径，并提供 生物体有办法消除脂溶性化学物质 他们被暴露了。 肝微粒体 UDP-葡萄糖醛酸转移酶 (UDPGT) 催化葡萄糖醛酸苷的形成。 我们实验室分离出了一种 这些蛋白质的数量对于缀合很重要 外源性物质和内源性物质。 肝小叶定位和分布的测定 对硝基苯酚 UDP-葡萄糖醛酸转移酶 (PNP-UDPGT)、17Beta-OH 类固醇 UDPGT 和 3Alpha-OH 类固醇 UDPGT 通过免疫组织化学分析是 计划。 使用特定抗体，研究将证明这些变化 分布在由各种试剂如3-甲基胆蒽产生的分布中。 此外，还将研究肝脏、胃肠道、肺和肾 来自拥有高水平 3Alpha-OH 类固醇 UDPGT (HA) 的 Wistar 大鼠和 低水平的 3Alpha-OH 类固醇 UDPGT (LA)。 这些研究将允许 了解细胞异质性在葡萄糖醛酸化中的作用。 实验将揭示PNP-UDPGT的N端氨基酸序列， 17β-OH类固醇UDPGT和3Alpha-OH类固醇UDPGT。 此外， 未经治疗的大鼠中这些转移酶表达的遗传调控 肝脏和用 3-甲基胆蒽治疗的大鼠肝脏中将 研究过。 3Alpha-OH类固醇UDPGT的遗传变异机制 将在 HA 和 LA Wistar 大鼠中进行研究。 吗啡的纯化和 将执行洋地黄毒甙元单洋地黄苷 UDPGT，然后，这些 将按照其他 UDPGT 的描述进一步研究酶。 将进行人肝脏 UDPGT 的纯化和表征。 磷脂需求、N端氨基酸序列实验 人肝脏UDPGT表达的基因调控是 计划。 最后，细胞异质性在人体组织中的作用将 使用免疫组织化学方法进行探索。 因此，如何以及在哪里 葡萄糖醛酸化的发生可以被探测和理解。