UDP GLUCURONOSYLTRANSFERASES IN PHARMACOLOGY

药理学中的 UDP 葡萄糖醛酸基转移酶

• 批准号: 6179091
• 负责人: THOMAS R TEPHLY
• 金额: $ 34.14万
• 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 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6179091
• 关键词: brain metabolism; cell line; chimeric proteins; drug interactions; drug metabolism; enzyme mechanism; enzyme substrate; gene expression; genetic polymorphism; glucuronosyltransferase; human tissue; immunocytochemistry; isozymes; laboratory rabbit; liver metabolism; losartan; morphine; protein structure function; site directed mutagenesis; western blottings; zidovudine

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.

葡萄糖醛酸苷的形成是人体内异生物质和内源性代谢的主要途径。UDP-葡糖醛酸糖基转移酶（UGT）是超基因家族的蛋白质产物，介导这些反应，由此疏水化合物（糖苷配基）与葡糖醛酸缀合，形成由肾脏或肝脏快速排泄的代谢物。计划开展四个研究领域。首先，将使用稳定表达这些蛋白质的HK 293细胞系探索UGT 2B 7的多态性同种型在某些底物（氯沙坦和齐多夫定）代谢中的意义。使用这些多态异构体纯合子个体的肝微粒体，研究将解决AZT葡萄糖醛酸化的个体间变异是否可以根据个体的基因型预测的问题。在人脑中发现了UGT 2B 7和UGT 1A 6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，以确定在大脑中表达这些蛋白质的细胞类型。由于免疫组织化学定位，以确定在大脑中表达这些蛋白质的细胞类型。由于UGT 2B 7催化吗啡-6-葡萄糖醛酸苷的形成（其作为镇痛剂的效力是吗啡的50倍），因此了解吗啡-6-葡萄糖醛酸苷可以在雨中形成是很重要的，因为其局部形成可能是吗啡作用机制的一部分。提出了确定肠中表达的UGT 1A 8和1A 5的底物特异性的研究。这些异构体在肝脏中不表达，因此，可能在肠道中的外源性和内源性代谢中发挥重要作用。UGT 1A 4是一种重要的酶，因为它催化叔胺（例如，抗组胺药）和孕激素，而UGT 1A 3催化雌激素和NSAID的葡萄糖醛酸化。建议研究UGT 1A 3和UGT 1A 4的蛋白质结构如何影响所表达的酶的功能。嵌合蛋白和氨基酸取代将检查糖苷配基结合位点的底物，所述底物对于每种蛋白是独特的并且对于每种UGT是共同的。