UDP GLUCURONOSYLTRANSFERASES IN PHARMACOLOGY

葡萄糖醛酸盐的形成是人体内外源性和内源性代谢的主要途径。udp -葡萄糖醛酸-糖基转移酶（UGTs）是一个超基因家族的蛋白质产物，介导这些反应，使疏水化合物（苷元）与葡萄糖醛酸结合，形成代谢产物，迅速由肾脏或肝脏排出体外。计划进行四个领域的研究。首先，我们将利用稳定表达UGT2B7和氯沙坦、齐多夫定等蛋白的HK293细胞系，探讨UGT2B7多态异构体在某些底物（氯沙坦和齐多夫定）代谢中的意义。使用来自个体的肝微粒体纯合这些多态性同型异构体，研究将解决是否可以根据个体的基因型预测AZT葡萄糖醛酸化的个体间差异的问题。在人脑中发现了UGT2B7和UGT1A6的mRNA和糖醛酸化活性。研究建议使用免疫组织化学定位来鉴定大脑中表达这些蛋白质的细胞类型。通过免疫组织化学定位来识别大脑中表达这些蛋白质的细胞类型。由于UGT2B7催化吗啡-6-葡萄糖醛酸盐的形成（吗啡作为镇痛药的效力是吗啡的50倍），因此了解吗啡-6-葡萄糖醛酸盐在雨中的形成位置是很重要的，因为它的局部形成可能解释了吗啡的部分作用机制。提出了确定在肠中表达的UGTs， 1A8和1A5的底物特异性的研究。这些异构体在肝脏中不表达，因此可能在肠道的外源性和内源性代谢中发挥重要作用。UGT1A4是一种重要的酶，因为它能催化叔胺（如抗组胺）和孕激素的糖醛酸化，而UGT1A3能催化雌激素和非甾体抗炎药的糖醛酸化。我们将研究UGT1A3和UGT1A4的蛋白结构如何影响其表达酶的功能。嵌合蛋白和氨基酸取代将检查底物的糖苷元结合位点，这些底物对每种蛋白质都是独特的，对每种UGT都是常见的。

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.