Ulrich P, Cerami A
The Kenneth S Warren, Laboratories, Tarrytown, New York 10591, USA.
Recent Prog Horm Res. 2001;56:1-21. doi: 10.1210/rp.56.1.1.
Biological amines react with reducing sugars to form a complex family of rearranged and dehydrated covalent adducts that are often yellow-brown and/or fluorescent and include many cross-linked structures. Food chemists have long studied this process as a source of flavor, color, and texture changes in cooked, processed, and stored foods. During the 1970s and 1980s, it was realized that this process, called the Maillard reaction or advanced glycation, also occurs slowly in vivo. Advanced glycation endproducts (AGEs) that form are implicated, causing the complications of diabetes and aging, primarily via adventitious and crosslinking of proteins. Long-lived proteins such as structural collagen and lens crystallins particularly are implicated as pathogenic targets of AGE processes. AGE formation in vascular wall collagen appears to be an especially deleterious event, causing crosslinking of collagen molecules to each other and to circulating proteins. This leads to plaque formation, basement membrane thickening, and loss of vascular elasticity. The chemistry of these later-stage, glycation-derived crosslinks is still incompletely understood but, based on the hypothesis that AGE formation involves reactive carbonyl groups, the authors introduced the carbonyl reagent aminoguanidine hydrochloride as an inhibitor of AGE formation in vivo in the mid 1980s. Subsequent studies by many researchers have shown the effectiveness of aminoguanidine in slowing or preventing a wide range of complications of diabetes and aging in animals and, recently, in humans. Since, the authors have developed a new class of agents, exemplified by 4,5-dimethyl-3-phenacylthiazolium chloride (DPTC), which can chemically break already-formed AGE protein-protein crosslinks. These agents are based on a new theory of AGE crosslinking that postulates that alpha-dicarbonyl structures are present in AGE protein-protein crosslinks. In studies in aged animals, DPTC has been shown to be capable of reverting indices of vascular compliance to levels seen in younger animals. Human clinical trials are underway.
生物胺与还原糖反应形成一系列复杂的重排和脱水共价加合物，这些加合物通常呈黄棕色和/或有荧光，并且包括许多交联结构。长期以来，食品化学家一直将此过程作为烹饪、加工和储存食品中风味、颜色和质地变化的一个来源进行研究。在20世纪70年代和80年代，人们认识到这个过程，即所谓的美拉德反应或晚期糖基化，在体内也会缓慢发生。形成的晚期糖基化终产物（AGEs）被认为是导致糖尿病并发症和衰老的原因，主要是通过蛋白质的偶然反应和交联。特别地，诸如结构胶原蛋白和晶状体晶状体蛋白等长寿蛋白质被认为是AGE过程的致病靶点。血管壁胶原蛋白中的AGE形成似乎是一个特别有害的事件，导致胶原蛋白分子彼此之间以及与循环蛋白质交联。这会导致斑块形成、基底膜增厚以及血管弹性丧失。这些后期糖基化衍生交联的化学性质仍未完全了解，但基于AGE形成涉及反应性羰基的假设，作者在20世纪80年代中期引入了羰基试剂盐酸氨基胍作为体内AGE形成的抑制剂。许多研究人员随后的研究表明，氨基胍在减缓或预防动物以及最近在人类中的多种糖尿病并发症和衰老方面是有效的。此后，作者开发了一类新的试剂，以4,5 - 二甲基 - 3 - 苯甲酰基噻唑鎓氯化物（DPTC）为例，它可以化学性地破坏已经形成的AGE蛋白质 - 蛋白质交联。这些试剂基于一种新的AGE交联理论，该理论假定α - 二羰基结构存在于AGE蛋白质 - 蛋白质交联中。在对老年动物的研究中，DPTC已被证明能够使血管顺应性指标恢复到年轻动物的水平。人体临床试验正在进行中。
