Reddy V N, Lin L R, Giblin F J, Lou M, Kador P F, Kinoshita J H
Eye Research Institute of Oakland University, Rochester, Michigan.
J Ocul Pharmacol. 1992 Spring;8(1):43-52. doi: 10.1089/jop.1992.8.43.
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) for possible clinical 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 cells. Based on ED50 values, dose required for 50% inhibition, the order of potencies against both HLE and HRPE enzymes was AL-4114 greater than AL-3152 greater than AL-1576 greater than tolrestat greater than statil greater than sorbinil. Since some ARIs are known to be bound to plasma proteins, it is conceivable that the observed differences in ED50 values 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 be maintained in serum-free media for short periods (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 activity against AR in HLE and HRPE cells.
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蓄积并导致水合作用，被认为是糖尿病性和半乳糖血症性白内障发病机制中的起始机制。AR还参与包括视网膜病变和神经病变在内的其他糖尿病并发症。因此，人们对开发有效的AR抑制剂（ARIs）用于人类糖尿病的可能临床应用兴趣浓厚。然而，对这些药物进行潜在临床应用评估时，需要在适当的靶组织中对化合物进行评估，因为已知来自不同组织的AR对ARIs表现出不同的敏感性。通过在高糖培养基中培养细胞72小时后，测量不同浓度ARI对半乳糖醇形成的抑制程度，研究了ARIs在人晶状体上皮细胞（HLE）和人视网膜色素上皮细胞（HRPE）中的相对疗效。无论所研究的ARIs的结构特征如何，与HLE细胞相比，抑制HRPE中多元醇合成需要更高的剂量。根据半数有效剂量（ED50）值，即50%抑制所需的剂量，对HLE和HRPE酶的效力顺序为AL-4114大于AL-3152大于AL-1576大于托瑞司他大于司他立大于索比尼尔。由于已知一些ARIs与血浆蛋白结合，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不同结合。通过使用犬晶状体上皮细胞（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短时间（4小时）维持。结果表明，无论有无血清，多元醇抑制程度相同，这表明抑制剂效力的差异可能反映了它们对HLE和HRPE细胞中AR的固有活性。
