INHIBITION OF ALDEHYDE REDUCTASE BY ALDOSE REDUCTASE INHIBITORS
INHIBITION OF ALDEHYDE REDUCTASE BY ALDOSE REDUCTASE INHIBITORS
复制标题
DOI：
10.1016/0006-2952(90)90490-c
复制
发表时间：
1990-09-01
影响因子：
5.8
通讯作者：
KADOR, PF
中科院分区：
文献类型：
--
作者：
SATO, S;KADOR, PF
已经检查了包括类黄酮、羧酸和乙内酰脲在内的一组结构不同的醛糖还原酶抑制剂抑制大鼠肾醛还原酶（EC 1.1.1.19，EC 1.1.1.20）与大鼠透镜醛糖还原酶（EC 1.1.1.21）的能力。所有检测的醛糖还原酶抑制剂在一定程度上抑制了还原反应中的醛还原酶，如用甘油醛作为底物和NADPH作为辅酶测定的，以及在氧化反应中，其中L-古洛糖酸在NADP+存在下氧化为D-葡萄糖醛酸。在所检测的抑制剂中，2，7-二氟螺芴-9，5“-咪唑烷-2”，4“-二酮（Al 1576）是最有效的抑制剂，仅需要在10- 8 M范围内的浓度就能抑制大鼠肾醛还原酶50%的体外活性（IC 50值），而3-二氧代-1-H-苯并[de]异喹啉-2（3 H）-乙酸（alrestatin）是效力最低的抑制剂，需要浓度在10-5 M范围内。这些醛糖还原酶抑制剂似乎同样抑制了还原和氧化步骤。此外，所有化合物似乎抑制粗品或高度纯化的大鼠肾醛还原酶基本上相同的程度。观察到这些抑制剂的选择性存在显著差异，表示为大鼠肾醛还原酶与以甘油醛为底物的大鼠透镜醛糖还原酶的IC 50值之比，对醛糖还原酶的选择性范围为约1000至约1000。2-A11576为119倍至3-（4-溴-2-氟苄基-4-氧代-3-酞嗪-1-基乙酸）（Ponalrestat）为119倍。动力学和竞争研究表明，这些抑制剂与醛还原酶在一个共同的网站，这是不相同的核苷酸结合位点的底物。这些结果表明，大鼠肾脏醛还原酶和醛糖还原酶的抑制剂结合位点包含几个共同的特点。
A broad group of structurally diverse aldose reductase inhibitors including flavonoids, carboxylic acids and hydantoins, have been examined for their ability to inhibit rat kidney aldehyde reductase (EC1.1.1.19, EC 1.1.1.20) versus rat lens aldose reductase (EC 1.1.1.21). All aldose reductase inhibitors examined inhibited aldehyde reductase to some extent both in the reductive reaction as determined with glyceraldehyde as substrate and NADPH as coenzyme, and in the oxidative reaction where L-gulonic acid was oxidized to D-glucuronic acid in the presence of NADP+. Of the inhibitors examined, 2,7-difluorospirofluorene-9,5''-imidazolidine-2'',4''-dione (Al1576) was the most potent inhibitor requiring only concentrations in the 10-8M range to inhibit 50% of the in vitro activity of rat kidney aldehyde reductase (IC50 value), whereas 3-dioxo-1-H-benz[de]isoquinoline-2(3H)-acetic acid (alrestatin) was the least potent inhibitor requiring concentrations in the 10-5 M range. Both the reductive and oxidative steps appeared equally inhibited by these aldose reductases inhibitors. Moreover, all compounds appeared to inhibit either crude or highly purfied rat kidney aldehyde reductase to essentially the same extent. Marked differences in the selectivity of these inhibitors, expressed as the ratio of IC50 values for rat kidney aldehyde reductase versus rat lens aldose reductase with glyceraldehyde as substrate, were observed with selectivity for aldose reductase ranging from ca. 2-fold for Al1576 to 119-fold for 3-(4-bromo-2-fluorobenzyl-4-oxo-3-phthalazine-1-ylacetic acid) (Ponalrestat). Kinetic and competition studies suggest that these inhibitors interact with aldehyde reductase at a common site that is not identical to either the substrate of nucleotide binding site. These results suggest that the inhibitor binding sites of rat kidney aldehyde reductase and aldose reductase contain several common characteristics.