UDP GLUCURONOSYLTRANSFERASES IN PHARMACOLOGY

葡萄糖醛酸苷的形成是人体异体和内生代谢的主要途径。UDP-葡萄糖醛-糖基转移酶(UGTS)是一个超基因家族的蛋白质产物，它介导这些反应，使疏水化合物(苷元)与葡萄糖醛酸结合，形成由肾脏或肝脏快速排泄的代谢物。计划进行四个领域的研究。首先，我们将使用稳定表达UGT2B7的HK293细胞株来探讨UGT2B7的多态异构体在某些底物(氯沙坦和齐多夫定)代谢中的意义。利用这些多态异构体纯合子个体的肝微粒体，研究将解决是否可以根据个体的基因预测AZT葡萄糖醛酸化反应的个体间差异的问题。在人脑中已经发现了UGT2B7和UGT1A6的mRNA和葡萄糖醛酸化活性。研究建议使用免疫组织化学定位来确定在大脑中表达这些蛋白质的细胞类型。自免疫组织化学定位以来，以确定在大脑中表达这些蛋白质的细胞类型。由于UGT2B7催化吗啡-6-葡萄糖醛酸化物的形成(其止痛剂的效力是吗啡的50倍)，因此重要的是要知道在雨中吗啡-6-葡萄糖醛酸化物可以在哪里形成，因为它的局部形成可能是吗啡作用机制的一部分。提出了确定在肠道表达的UGT的底物特异性的研究，即1A8和1A5。这些异构体在肝脏中不表达，因此可能在肠道的异生和内生代谢中发挥重要作用。UGT1A4是一种重要的酶，因为它催化叔胺(如抗组胺)和孕激素的葡萄糖醛酸化反应，而UGT1A3催化雌激素和非甾体抗炎药的葡萄糖醛酸化反应。研究将调查UGT1A3和UGT1A4的蛋白质结构如何影响所表达的酶的功能。嵌合蛋白质和氨基酸替换将检查底物的苷元结合位置，底物是每种蛋白质独有的，每种UGT都是共同的。

Glucuronide formation is a major route of xenobiotic and endobiotic metabolism in humans. UDP-glucuron-osyltransferases (UGTs), protein products of a supergene family, mediate these reactions whereby hydrophobic compounds (aglycones) are conjugated to glucuronic acid, forming metabolites which are rapidly excreted by the kidney or liver. Four areas of research are planned. First, the significance of the polymorphic isoforms of UGT2B7 in the metabolism of certain substrates (losartan and zidovudine) will be explored using HK293 cell lines stable expressing these proteins. Using hepatic microsomes from individuals homozygous for these polymorphic isoforms, studies will address the question of whether inter-individual variation in AZT glucuronidation can be predicted base don the genotype of the individual. mRNA and glucuronidation activities for UGT2B7 and UGT1A6 have been found in human brain. Studies are proposed to use immunohistochemical localization to identify the cell types that express these proteins in the brain. Since immunohistochemical localization to identify the cell types that express these proteins in the brain. Since UGT2B7 catalyzes the formation of morphine-6-glucuronide (which is 50 times more potent that morphine as an analgesic) it is important to know where in the rain morphine-6-glucuronide can be formed because its local formation may account for part of the mechanism of action of morphine. Studies determining the substrate specificities of UGTs expressed in intestine, 1A8 and 1A5, are proposed. These isoforms are not expressed in liver and, therefore, may play an important role in xenobiotic and endobiotic metabolism in the intestine. UGT1A4 is an important enzyme because it catalyzes the glucuronidation of tertiary amines (e.g., anti-histamines) and progestins, whereas UGT1A3 catalyzes the glucuronidation of estrogens and NSAIDs. Studies are proposed that will investigate how the protein structure of UGT1A3 and UGT1A4 affects the function of the expressed enzymes. Chimeric proteins and amino acid substitutions will examine the aglycone binding sites for substrates which are unique to each protein and which are common for each UGT.