4-Hydroxyretinoic acid, a novel substrate for human liver microsomal UDP-glucuronosyltransferase(s) and recombinant UGT2B7
4-Hydroxyretinoic acid, a novel substrate for human liver microsomal UDP-glucuronosyltransferase(s) and recombinant UGT2B7
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DOI：
10.1074/jbc.275.10.6908
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发表时间：
2000-03-10
影响因子：
4.8
通讯作者：
Radominska-Pandya, A
中科院分区：
文献类型：
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作者：
Samokyszyn, VM;Gall, WE;Radominska-Pandya, A
研究表明，全反式维甲酸（atRA）通过氧化途径形成极性更强的代谢产物限制了其生物活性。在这份报告中，我们研究了生物转化的氧化产物的atRA通过葡萄糖醛酸化。为此，我们合成了放射性和非放射性形式的4-羟基-RA（4-OH-RA）、4-羟基-视黄酯乙酸酯（4-OH-RAc）和5，6-环氧-RA，它们都是atRA氧化的主要产物。这些类维生素A的人肝微粒体和人重组UDP-葡萄糖醛酸转移酶（UGT）的葡萄糖醛酸化的特点和比较与葡萄糖醛酸化的atRA。人肝微粒体葡萄糖醛酸化4-OH-RA和4-OH-RAc的活性分别比atRA高6倍和3倍。葡萄糖醛酸化产物的分析表明，4-OH-RA和4-OH-RAc的羟基连接的葡萄糖醛酸苷是主要产物，而不是与atRA、4-oxo-RA和5，6-epoxy-RA形成羧基连接的葡萄糖醛酸苷。我们还确定了人重组UGT 2B 7可以葡萄糖醛酸化atRA、4-OH-RA和4-OH-RAc，其活性与人肝微粒体中发现的活性相似。因此，我们推测，这种人类同工酶，这是在人类肝脏，肾脏和肠道中表达，发挥了关键作用的生物命运的atRA。我们还提出，atRA诱导其自身的氧化代谢，通过细胞色素P450（CYP 26），并进一步生物转化为葡萄糖醛酸通过UGT介导的途径。
It is suggested that formation of more polar metabolites of all-trans-retinoic acid (atRA) via oxidative pathways limits its biological activity. In this report, we investigated the biotransformation of oxidized products of atRA via glucuronidation. For this purpose, we synthesized 4-hydroxy-RA (4-OH-RA) in radioactive and nonradioactive form, 4-hydroxy-retinyl acetate (4-OH-RAc), and 5,6-epoxy-RA, all of which are major products of atRA oxidation. Glucuronidation of these retinoids by human liver microsomes and human recombinant UDP-glucuronosyltransferases (UGTs) was characterized and compared with the glucuronidation of atRA. The human liver microsomes glucuronidated 4-OH-RA and 4-OH-RAc with 6- and 3-fold higher activity than atRA, respectively. Analysis of the glucuronidation products showed that the hydroxyl-linked glucuronides of 4-OH-RA and 4-OH-RAc were the major products, as opposed to the formation of the carboxyl-linked glucuronide with atRA, 4-oxo-RA, and 5,6-epoxy-RA. We have also determined that human recombinant UGT2B7 can glucuronidate atRA, 4-OH-RA, and 4-OH-RAc with activities similar to those found in human liver microsomes. We therefore postulate that this human isoenzyme, which is expressed in human liver, kidney, and intestine, plays a key role in the biological fate of atRA. We also propose that atRA induces its own oxidative metabolism via a cytochrome P450 (CYP26) and is further biotransformed into glucuronides via UGT-mediated pathways.