Beyer-Mears A, Diecke F P, Mistry K, Ellison C, Cruz E
Department of Pharmacology and Physiology, UMDNJ, New Jersey Medical School, Newark 07103-2714, USA.
Pharmacology. 1997 Aug;55(2):78-86. doi: 10.1159/000139515.
In diabetic cataract, sorbitol pathway flux perturbs intracellular metabolism by two putative mechanisms. The osmolyte hypothesis implicates the aldose reductase enzyme, increased rate of reduction of glucose of sorbitol and reciprocal osmoregulatory depletion of organic osmolytes (myo-inositol). Redox hypothesis favors alterations in the ratios (NADP+/NADPH and/or NADH/NAD+ as the primary cause of glucose-induced aldose reductase related defects. Increase in NADH/NAD+ promotes increased oxidation of sorbitol to fructose by polyol dehydrogenase; potential normalization of this ratio by coadministration of pyruvate (which reoxidizes NADH to NAD+ via lactate dehydrogenases reaction) was investigated. Effects of exogenous pyruvate on lens polyol formation and sodium-dependent myo-inositol (MI) cotransporter using two in vitro models of sugar cataract were determined. Rat lenses were incubated for 16 h in either normal (5.5 mM) or high sugar medium, 35.5 mM glucose or 30 mM galactose. Then lens MI influx was compared to polyol, MI and fructose content. Pyruvate did not affect MI influx or sorbitol content in lenses incubated in control medium. In 35.5 mM glucose, coadministration of pyruvate maintained lens MI influx at 76% of control values vs. 43% for lenses without pyruvate. Furthermore, pyruvate treatment diminished lens sorbitol content by 50% and increased lens sugar content (myo-inositol, fructose, lactate) and media lactate levels. Lenses incubated in high galactose medium formed galactitol with a corresponding decreased MI content. Coadministration of pyruvate had no effect on either lens sugar content (galactitol, myo-inositol, fructose) or MI influx, consistent with the fact that galactitol was not metabolized to fructose. In conclusion, pyruvate did not exert a direct effect on the MI co-transporter or prevent galactitol inhibition of MI influx. Coadministration of pyruvate with high glucose altered lens metabolism and promoted reduction of pyruvate to lactate, increased fructose, decreased sorbitol, enhanced MI influx, maintained lens MI content, implicating both osmotic and redox systems.
在糖尿病性白内障中，山梨醇途径通量通过两种假定机制扰乱细胞内代谢。渗透溶质假说涉及醛糖还原酶、葡萄糖还原为山梨醇的速率增加以及有机渗透溶质（肌醇）的相互渗透调节耗竭。氧化还原假说认为比率的改变（NADP⁺/NADPH和/或NADH/NAD⁺）是葡萄糖诱导的醛糖还原酶相关缺陷的主要原因。NADH/NAD⁺的增加促进了多元醇脱氢酶将山梨醇氧化为果糖；研究了通过同时给予丙酮酸（其通过乳酸脱氢酶反应将NADH再氧化为NAD⁺）使该比率潜在正常化的情况。使用两种糖性白内障体外模型确定了外源性丙酮酸对晶状体多元醇形成和钠依赖性肌醇（MI）共转运体的影响。将大鼠晶状体在正常（5.5 mM）或高糖培养基（35.5 mM葡萄糖或30 mM半乳糖）中孵育16小时。然后比较晶状体MI流入量与多元醇、MI和果糖含量。丙酮酸对在对照培养基中孵育的晶状体的MI流入量或山梨醇含量没有影响。在35.5 mM葡萄糖中，同时给予丙酮酸可使晶状体MI流入量维持在对照值的76%，而未给予丙酮酸的晶状体为43%。此外，丙酮酸处理使晶状体山梨醇含量降低50%，并增加了晶状体糖含量（肌醇、果糖、乳酸）和培养基乳酸水平。在高半乳糖培养基中孵育的晶状体形成半乳糖醇，相应地MI含量降低。同时给予丙酮酸对晶状体糖含量（半乳糖醇、肌醇、果糖）或MI流入量均无影响，这与半乳糖醇未代谢为果糖的事实一致。总之，丙酮酸对MI共转运体没有直接作用，也不能防止半乳糖醇对MI流入的抑制。丙酮酸与高糖同时给药改变了晶状体代谢，促进了丙酮酸还原为乳酸，增加了果糖，减少了山梨醇，增强了MI流入，维持了晶状体MI含量，涉及渗透和氧化还原系统。
