Glycoxidation Products (GOP), also known as Malillard or advanced glycation end products (AGE), occur in nature and their formation is greatly enhanced during the cooking and heating of foods. Derived from nonenzymatic reactions between reducing sugars and free NH2-groups of proteins and lipids, GOPs are known to include reactive oxygen species (ROS) and cross linking moieties. However, their life-long toxic impact on body tissues due to oral absorption of good-GOPs has not been appreciated. GOPs are also endogenously produced from blood glucose and are implicated in the development of vascular and renal tissue damage associated with aging and accelerated with diabetes. The toxicity of GOP has been best exemplified in studies in which their administration to normal animals induced ROS, enhanced cytokine and growth factor release, and pathophysiologic changes consistent with vascular and renal disease. Monocyte/macrophages, endothelium and other cells express a cell-surface GOP binding and internalizing receptor system, linked to ROS-mediated cell activation, growth-promoting mediator production and matrix synthesis, consequently leading to profoundly altered vascular and renal structure/function. We have found that food-GOP are orally absorbed, maintain chemical properties in circulation, and their normally limited renal excretion, (about 30% of absorbed) is reduced to <5% in patients with severe renal disease. Thus, the constant influx of food-GOP may constitute a previously unrecognized environmental health risk factor, especially for those individuals susceptible to vascular and renal disease. The goals of this proposal are to explore: 1a. The cellular processing of food-GOP and their effects on cytokine/growth factor gene regulation in vitro; 1b. The in vivo turnover and tissue effects of food-GOP in animals with normal and genetically altered renal function (non-diabetic NOD mice); and 2. The intracellular effects of, and contribution of food-GOP to, cellular activation and signal transduction. These studies will encompass the interrelationships between these unrecognized environmental toxins, ROS-related oxidative damage, and key cellular systems: finding the critical molecular signaling processes linked to oxidant stress, abnormal responses and toxicity is likely to lead to therapeutic approaches to interfere specifically with their adverse effects on the vascular/renal system of the general population.
