UDP-GLUCURONOSYLTRANSFERASES IN PHARMACOLOGY

药理学中的 UDP-葡萄糖醛酸基转移酶

• 批准号: 2174656
• 负责人: THOMAS R TEPHLY
• 金额: $ 19.96万
• 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 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2174656
• 关键词: active sites; affinity labeling; brain metabolism; catechols; chickens; clone cells; complementary DNA; detoxification; drug interactions; drug metabolism; enzyme substrate; estrogens; gene expression; glucuronosyltransferase; human tissue; laboratory rabbit; laboratory rat; liver metabolism; molecular cloning; morphine; protein structure function; tertiary amine; uridine diphosphate

The process of glucuronide formation leads to the formation of hydrophilic metabolites which are readily excreted by the kidney and liver. This serves as an important regulatory mechanism for the termination of drug and endobiotic action and as a detoxification mechanism in the case of xenobiotic exposure. Enzymes catalyzing glucuronidation have been shown to be products of a supergene family; these are termed UDP- glucuronosyltransferases (UGTs). The objectives of this application are to continue studies directed at an understanding of the structure and function of UGTs which catalyze the glucuronidation of morphine, other opioid agonists or antagonists and non-opioid tertiary amines, such as, antidepressants, antihistamines and antipsychotics whose metabolism leads to the major quaternary ammonium glucuronide excretory products in humans. In addition, studies are proposed to explore the function of a UGT that is abundant in human liver which catalyzes aromatic carcinogenic amine glucuronidation. mRNA for a steroid reactive UGT human liver (UGT2B15) has been discovered in brain. Since this protein catalyzes estrogen catechol glucuronidation and since estrogen catechols present in brain have important biological functions, such as hormonal release from the pituitary, studies have been designed to characterize the brain regions which might be involved in the UGT2B15-mediated glucuronidation of steroid hormones such as the estrogens and their catechol derivatives. Since morphine glucuronidation has been shown in human brain, UGTs involved in human brain metabolism of morphine will also be studied. Techniques involving molecular cloning and expression of cDNAs in human embryonic kidney (HK)293 cells will be used as the isolated relevant UGT cDNAs are isolated. Specific oligonucleotide and antibody probes will be available to assist in accomplishing the aims and objectives proposed in the application. Over 200 substances including drugs, steroids, simple phenols, monoterphenoids, bulky aliphatic alcohols, flavonoids, coumarins, and bilirubin will be tested as substrates for UGT cDNA encoded protein products. The observation that many UGTs, including those isolated in this laboratory, react with many natural plant-derived products often present in the diet as well as drugs and endobiotics indicates that the research proposed in this application will provide information, not only on potential drug-drug interaction, but on possible drug-natural product interaction.

葡萄糖醛酸苷形成的过程导致亲水性的形成 代谢产物很容易被肾脏和肝脏排泄。 这 作为药物终止的重要调节机制 和内生作用并作为解毒机制 外源性物质暴露。 催化葡萄糖醛酸化的酶已被证明 是超基因家族的产物；这些被称为 UDP- 葡萄糖醛酸基转移酶（UGT）。 该应用程序的目标是 继续研究以了解结构和 UGT 的功能，催化吗啡等的葡萄糖醛酸化 阿片类激动剂或拮抗剂和非阿片类叔胺，例如， 代谢导致的抗抑郁药、抗组胺药和抗精神病药 人类主要的季铵葡萄糖醛酸排泄产物。 此外，还提出了研究探索 UGT 的功能，即 人体肝脏中含量丰富，可催化芳香致癌胺 葡萄糖醛酸化。 类固醇反应性 UGT 人肝脏 (UGT2B15) 的 mRNA 在大脑中被发现。 由于这种蛋白质可以催化雌激素 儿茶酚葡萄糖醛酸化和由于雌激素儿茶酚存在于大脑中 具有重要的生物学功能，例如从体内释放荷尔蒙 垂体，研究旨在描述大脑区域的特征 可能参与 UGT2B15 介导的类固醇葡萄糖醛酸化 激素，例如雌激素及其儿茶酚衍生物。 自从 吗啡葡萄糖醛酸化已在人脑中得到证实，UGT 参与 人脑对吗啡的代谢也将被研究。 技巧 涉及人类胚胎中 cDNA 的分子克隆和表达 将使用肾 (HK)293 细胞，因为分离的相关 UGT cDNA 是 孤立。 将提供特定的寡核苷酸和抗体探针 协助实现《建议》中提出的宗旨和目标 应用。 超过 200 种物质，包括药物、类固醇、简单物质 酚类、单萜类、大体积脂肪醇、类黄酮、香豆素、 胆红素将作为 UGT cDNA 编码蛋白的底物进行测试 产品。 观察到许多 UGT，包括那些在 该实验室经常与许多天然植物衍生产品发生反应 饮食以及药物和内生素中的存在表明 本申请中提出的研究将提供信息，不仅 潜在的药物-药物相互作用，以及可能的药物-天然产物 相互作用。