UDP-GLUCURONOSYLTRANSFERASES IN PHARMACOLOGY

葡萄糖醛酸苷的形成过程导致亲水性的形成 肾脏和肝脏容易排泄的代谢物。这 作为终止药物的重要监管机制 和内生作用，并作为一种解毒机制 异种生物暴露。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)。此应用程序的目标是 继续研究以了解结构和 催化吗啡葡萄糖醛酸化的UGT功能，其他 阿片类激动剂或拮抗剂和非阿片类叔胺，例如， 新陈代谢导致抗抑郁药、抗组胺药和抗精神病药物 人体内主要的季铵盐葡糖醛酸类排泄物。 此外，还提出了探索UGT功能的研究，即 人体肝脏中富含催化芳香族致癌胺的物质 葡萄糖醛酸化反应。类固醇反应性UGT人肝脏(UGT2B15)的mRNA 已经在大脑中被发现。因为这种蛋白质催化雌激素 儿茶酚糖醛酸化与脑内雌激素引起的儿茶酚 具有重要的生物学功能，例如从 脑下垂体的研究已经被设计来描述大脑区域的特征 可能参与UGT2B15介导的类固醇葡醛酸化反应 激素，如雌激素及其儿茶酚的衍生物。自.以来 已在人脑中显示出吗啡葡萄糖醛酸化，UGT参与了 人类大脑对吗啡的新陈代谢也将被研究。技术 涉及人胚胎中cDNA的分子克隆和表达 将使用肾(香港)293细胞作为分离的相关UGT cDNA 与世隔绝。将提供特定的寡核苷酸和抗体探针 协助完成《 申请。超过200种物质，包括药物、类固醇、简单 酚类，单萜类，大体积脂肪醇类，类黄酮类，香豆素， 胆红素将作为UGT基因编码蛋白的底物进行测试 产品。观察到许多UGT，包括那些孤立在 这个实验室经常与许多天然植物衍生产品发生反应 在饮食以及药物和内生菌中的存在表明 本申请中提出的研究将提供信息，而不仅仅是 关于潜在的药物-药物相互作用，但关于可能的药物-天然产物 互动。

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.