UDP-GLUCURONYLTRANSFERASES

UDP-葡萄糖醛酸转移酶

• 批准号: 3273720
• 负责人: THOMAS R TEPHLY
• 金额: $ 22.8万
• 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 1991-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3273720
• 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.

葡糖苷酸缀合是药物代谢的主要途径， 一种消除脂溶性化学物质的方法， 他们就暴露了 肝微粒体UDP-葡萄糖醛酸转移酶（UDPGTs） 催化葡糖苷酸的形成。 我们的实验室分离出了一种 这些蛋白质的数量，这是重要的共轭 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），17 β-OH类固醇 UDPGT和3 α-OH类固醇UDPGT通过免疫组织化学分析， 计划好了 使用特异性抗体，研究将证明这些变化 在分布中由各种试剂如3-甲基胆蒽产生。 此外，还将研究肝脏、胃肠道、肺和肾脏 来自具有高水平3 α-OH类固醇UDPGT（HA）的Wistar大鼠， 低水平的3Alpha-OH类固醇UDPGT（LA）。 这些研究将使 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-末端氨基酸序列， 17 β-OH类固醇UDPGT和3 α-OH类固醇UDPGT。 此外该 未处理大鼠中这些转移酶表达的遗传调节 肝脏和用3-甲基胆蒽处理的大鼠的肝脏中， 研究了 3 α-OH甾体类化合物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 将进行洋地黄毒苷单洋地黄毒苷UDPGTs，然后，这些 将如对其它UDPGT所述进一步研究酶。 将进行人肝脏UDPGTs的纯化和表征。 磷脂需求实验，N-末端氨基酸序列 人肝UDPGT表达的遗传调控是 计划好了 最后，细胞异质性在人体组织中的作用将 用免疫组织化学方法进行研究。 因此，如何以及在何处 葡萄糖醛酸化的发生可以被探测和理解。