The efficacy of aldose reductase inhibitors on polyol accumulation in human lens and retinal pigment epithelium in tissue culture.
The efficacy of aldose reductase inhibitors on polyol accumulation in human lens and retinal pigment epithelium in tissue culture.
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醛糖还原酶抑制剂对组织培养物中人晶状体和视网膜色素上皮中多元醇积累的功效。
DOI：
10.1089/jop.1992.8.43
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发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Kinoshita,JH
中科院分区：
文献类型：
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作者：
Reddy,VN;Lin,LR;Giblin,FJ;Lou,M;Kador,PF;Kinoshita,JH
由醛糖还原酶（AR）介导的过量糖醇的形成及其在晶状体中的细胞内积累以及由此产生的水合作用被认为是糖尿病和半乳糖性白内障发病机制的起始机制。 AR 还与其他糖尿病并发症有关，包括视网膜病变和神经病变。因此，人们对开发有效的 AR 抑制剂（ARIs）以用于人类糖尿病的临床应用产生了浓厚的兴趣。然而，评估这些药物的潜在临床用途需要在适当的靶组织中评估这些化合物，因为已知来自不同组织的 AR 对 ARI 表现出不同的敏感性。通过测量细胞在高半乳糖培养基中孵育 72 小时后不同浓度的 ARI 对半乳糖醇形成的抑制程度，研究了 ARI 在人晶状体上皮 (HLE) 和人视网膜色素上皮 (HRPE) 中的相对功效。无论所研究的 ARI 的结构特征如何，与 HLE c50 相比，需要更高的剂量来抑制 HRPE 中的多元醇合成。根据 ED<50 值、50% 抑制所需的剂量，针对 HLE 和 HRPE 酶的效力顺序为 AL-4114 > AL-3152e > AL-1576 > tolrcstat > statil > sorbinil。由于已知某些 ARI 与血浆蛋白结合，因此可以想象观察到的 ED50 值差异可能是由于与培养基中血清蛋白的结合差异所致。通过使用狗晶状体上皮（DLE）培养物来检验这种可能性。这些细胞合成的半乳糖醇水平比 HLE 和 HRPE 高得多，可以在无血清培养基中维持较短的时间（4 小时）。结果表明，在存在或不存在血清的情况下，多元醇的抑制程度是相同的，这表明抑制剂效力的差异可能反映了它们在 HLE 和 HRPE 细胞中对抗 AR 的固有活性。
The formation of excess sugar alcohol mediated by aldose reductase (AR) and its intracellular accumulation in lens with resultant hydration is thought to be the initiating mechanism in the pathogenesis of diabetic and galactosemic cataracts. AR is also involved in other diabetic complications including retinopathy and neuropathy. Therefore, there is heightened interest in developing effective AR inhibitors (ARIs) fr possble clnica use in human diabetes. However, the evaluation of these drugs for potential clinical use requires that the compounds be evaluated in appropriate target tissues since AR from different tissues is known to exhibit differential susceptibility to ARIs. The relative efficacy of ARIs in human lens epithelium (HLE) and human retinal pigment epithelium (HRPE) was studied by measuring the degree of inhibition of galactitol formation at various concentrations of ARI following incubation of cells in high galactose media for 72 hrs. Regardless of the structural characteristics of the ARIs investigated, higher doses were required to inhibit polyol synthesis in HRPE as compared to HLE c50s. Based on ED<50values, dose required for 50% inhibition, the order of potencies against both HLE and HRPE enzymes was AL-4114 > AL-3152e> AL-1576 > tolrcstat > statil > sorbinil. Since some ARIs are known to be bound to plasma proteins, it is conceivable that the observed differences in ED50values could be due to differential binding to serum proteins in the culture medium. This possibility was examined by employing cultures of dog lens epithelium (DLE). These cells, which synthesize much higher levels of galactitol than HLE and HRPE, could e maintaine in serm-free medi for hort peiods (4 hrs) of time. The results, which demonstrate that the extent of polyol inhibition was the same in the presence or absence of serum, suggest that the differences in the potency of the inhibitors may reflect their inherent ativity against AR in HLE and HRPE cells.