Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3.
Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3.
复制标题
DOI：
--
复制
发表时间：
1998-06
期刊：
影响因子：
--
通讯作者：
Mitchell D. Green;C. King;B. Mojarrabi;P. Mackenzie;T. Tephly
中科院分区：
文献类型：
--
作者：
Mitchell D. Green;C. King;B. Mojarrabi;P. Mackenzie;T. Tephly
含有叔胺部分的外源物质的葡萄糖醛酸结合代表了这些化合物在人体中独特且重要的代谢途径。此前，人 UDP-葡萄糖醛酸基转移酶 (UGT) 1A4 被证明是形成季铵连接的葡萄糖醛酸苷的重要酶。 UGT1A3 与 UGT1A4 的一级氨基酸序列有 93% 的同一性。我们发现，在人胚胎肾 293 细胞中瞬时表达的人 UGT1A3 也能催化伯胺、仲胺和叔胺底物（例如 4-氨基联苯、二苯胺和赛庚啶）的 N-葡萄糖醛酸化。与表达的人UGT1A4高效催化胺的葡萄糖醛酸化相比，UGT1A3催化的胺的葡萄糖醛酸化效率较低，表明UGT1A3对这些化合物的代谢消除仅做出有限的贡献。还检查了表达的人 UGT1A3 对羟基化和含羧酸化合物的反应性。除了胺之外，表达的人UGT1A3还催化阿片类药物（例如吗啡和丁丙诺啡）、香豆素、类黄酮（例如柚皮素和槲皮素）、蒽醌和小酚类化合物（例如4-硝基苯酚）的葡萄糖醛酸化。含有羧酸部分的药物，例如非甾体类抗炎药（例如萘普生和布洛芬）和贝特类药物（例如环丙贝特），是人 UGT1A3 的底物。相反，含有脂肪族羟基的化合物，例如皂苷元、单萜醇（例如薄荷醇和冰片）和雄激素，不被表达的人UGT1A3缀合。在测试的化合物中，东莨菪素、柚皮素和去甲丁丙诺啡似乎是人 UGT1A3 的最佳外源底物。
Glucuronide conjugation of xenobiotics containing a tertiary amine moiety represents a unique and important metabolic pathway for these compounds in humans. Previously, human UDP-glucuronosyltransferase (UGT) 1A4 was shown to be an important enzyme for the formation of quaternary ammonium-linked glucuronides. UGT1A3 is 93% identical to UGT1A4 in primary amino acid sequence. We show that human UGT1A3, transiently expressed in human embryonic kidney 293 cells, also catalyzes the N-glucuronidation of primary, secondary, and tertiary amine substrates, such as 4-aminobiphenyl, diphenylamine, and cyproheptadine. In contrast to expressed human UGT1A4, which catalyzes the glucuronidation of amines with high efficiency, glucuronidation of amines catalyzed by UGT1A3 exhibited low efficiency, suggesting that UGT1A3 makes only a limited contribution to the metabolic elimination of these compounds. The reactivity of expressed human UGT1A3 toward hydroxylated and carboxylic acid-containing compounds was also examined. In addition to amines, expressed human UGT1A3 catalyzed the glucuronidation of opioids (e.g. morphine and buprenorphine), coumarins, flavonoids (e.g. naringenin and quercetin), anthraquinones, and small phenolic compounds (e.g. 4-nitrophenol). Drugs containing a carboxylic acid moiety, such as nonsteroidal anti-inflammatory agents (e.g. naproxen and ibuprofen) and fibrates (e.g. ciprofibrate), were substrates for human UGT1A3. In contrast, compounds containing an aliphatic hydroxyl group, such as sapogenins, monoterpenoid alcohols (e.g. menthol and borneol), and androgens, were not conjugated by expressed human UGT1A3. Of the compounds tested, scopoletin, naringenin, and norbuprenorphine appeared to be the best xenobiotic substrates for human UGT1A3.