醛糖还原酶在糖尿病性白内障中的作用

The Role of Aldose Reductase in Diabetic Cataract

醛糖还原酶(aldose reductase,AR)是糖代谢多元醇(山梨醇)通路的第一个关键酶。在哺乳动物细胞中,正常血糖(3.8-6.1mmol/L)下,细胞中的葡萄糖主要由己糖激酶将其磷酸化转化为葡萄糖-6-磷酸,并进入糖酵解途径。只有微量的非磷酸化的葡萄糖(约3%)进入多元醇通路。然而,在高血糖状态(>7 mmol/L)下,大于30%的葡萄糖通过多元醇途径代谢。多元醇途径中的第一步反应是由AR催化的还原型烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate,NADPH)依赖性还原反应,将葡萄糖还原为山梨醇,并消耗NADPH。第二步反应是由山梨醇脱氢酶催化烟酰胺腺嘌呤二核苷酸(Nicotinamide Adenine Dinucleotide,NAD)依赖性氧化反应,将山梨醇氧化为果糖,并消耗NAD产生NADH。AR在糖尿病性白内障形成过程中扮演着重要的角色,AR活性增高可以引发细胞内渗透压的改变,非酶糖基化的激活,氧化应激等,不同结构的AR抑制剂可以有效的阻止白内障的形成。本文主要对AR引起的这些改变在糖尿病性白内障形成过程中参与的机制以及AR抑制剂的研发与应用进行综述。

Aldose reductase （AR） is the key enzyme of the glucose metabolism polyhydric Talcohols （sorbitol） pathway. In mammalian cells, under normoglycemia （3.8-6.1 mmol/L）, cellular glucose is predominantly phosphorylated into glucose 6-phosphate by hexokinase, and enters the glycolytic pathway. Only trace amounts of non-phosphorylated glucose （about 3%） enters the polyol pathway. However, under hyperglycemic condition （〉 7 mmol/L）, there is increased flux that enters the polyol pathway, accounting for greater than 30% of glucose metabolism. The fist step of the polyol pathway is the NADPH-dependent reduction of glucose to sorbitol catalyzed by AR, at the expense of reduced NADPH. The second step of the polyol pathway is NAD-dependent oxidation by sorbitol dehydrogenase, Sorbitol is converted to fructose and NAD convert into NADH. The polyol AR plays an important role in diabetic cataract formation, AR activity increased can lead to intracellular osmotic pressure changes, activation of non- enzymatic glycation and oxidative stress e.g., Structurally diverse AR inhibitors can effectively prevent cataract formation. This article mainly review these changes caused by the AR mechanisms involved in diabetic cataract pathogenesis and the aldose reductase inhibitor＇s development and application.