THE PHYSIOLOGICAL IMPACT OF AMINO ACID SUPPLEMENTS: INTERACTION WITH BASAL FORMATION OF ADVANCED GLYCATION ENDPRODUCTS

简介：精氨酸等氨基酸被许多健康人用作口服补充剂，但其生理影响尚未详细研究。精氨酸是一种基本的半必需氨基酸，部分来源于饮食。L-精氨酸参与几种代谢途径，是几种酶的底物，包括一氧化氮合酶，其形成一氧化氮、血管扩张剂和神经调节剂。它也转化为鸟氨酸，使氨解毒。肌酸是L-精氨酸的另一种代谢产物，促进Na+泵活性和中枢神经递质释放。精氨酸脱羧酶从L-精氨酸产生胍丁胺。口服精氨酸对这些代谢途径和酶的影响尚不清楚。我们已经证明，精氨酸的L-和D-异构体都是由葡萄糖和果糖代谢产生的反应性醛-丙酮醛（MG）。MG也是晚期糖基化终产物（AGEs）的主要前体。MG和AGEs在健康人中以低水平产生，并有助于正常的衰老过程。它们的水平在糖尿病状态下升高。该研究项目旨在提高我们对氨基酸补充剂（如精氨酸和半胱氨酸，另一种MG清除剂）对其代谢酶和途径以及基础MG和AGEs形成过程的影响的认识。该计划旨在将这些研究扩展到人类志愿者和人类生理学。 替代品和方法：短期目标是确定口服L-精氨酸和D-精氨酸对其代谢酶和途径的影响，以及MG和AGEs的基础水平。D-精氨酸是MG清除剂，但不是使用L-精氨酸的各种酶的底物，将用作对照。将在雄性和雌性Sprague-Dawley大鼠体内以及从这些大鼠中采集的分离组织和器官中进行体外研究。该方案将检查L-和D-精氨酸急性单次给药以及慢性4周或16周给药的影响。将从文献中报告的剂量范围的下限和上限中选择两种口服剂量。我的研究计划的长期目标是研究这些氨基酸对碳水化合物和脂肪酸代谢途径的影响，以及对MG和AGEs产生的分子机制的影响，最初在动物（大鼠）中，随后在人类中。在我的研究计划中感兴趣的其他氨基酸是半胱氨酸和赖氨酸，由于它们对MG具有很大的亲和力，并且可能对MG和AGEs形成的生理学产生影响。 结果：我的研究结果将有助于推进对口服L-和D-精氨酸以及其他氨基酸的生理影响的认识，并建立它们在动物和人类中的代谢命运。精氨酸和半胱氨酸与MG和AGEs形成的生理过程的有益相互作用可能会鼓励研究用所研究的氨基酸强化正常饮食。

INTRODUCTION: Amino acids such as arginine are used as oral supplements by many healthy people, yet their physiological impact has not been studied in detail. Arginine is a basic semi-essential amino acid partly derived from the diet. L-arginine is involved in several metabolic pathways and is a substrate for several enzymes, including nitric oxide synthase, which forms nitric oxide, a vasodilator and neuromodulator. It is also converted to ornithine, which enables ammonia detoxification. Creatine, another metabolite of L-arginine, facilitates Na+ pump activity and central neurotransmitter release. Arginine decarboxylase produces agmatine from L-arginine. The impact of oral arginine on these metabolic pathways and enzymes is not known. We have shown that both L- and D-isomers of arginine scavenge methylglyoxal (MG), a reactive aldehyde generated by glucose and fructose metabolism. MG is also a major precursor of advance glycation endproducts (AGEs). MG and AGEs are produced at low levels in healthy people and contribute to the normal aging process. Their levels are elevated in diabetic states. The research project is designed to advance our knowledge on the impact of amino acid supplements, such as arginine and cysteine, another MG scavenger, on their metabolic enzymes and pathways and the process of basal MG and AGEs formation. The program aims to extend these studies to human volunteers and human physiology. OBJECTIVES AND METHODS: The short-term objective is to determine the impact of oral L-arginine and D-arginine on their metabolic enzymes and pathways, and the basal levels of MG and AGEs. D-arginine, a MG scavenger but not a substrate for the various enzymes that use L-arginine, will serve as a control. The studies will be carried out in vivo in male and female Sprague-Dawley rats and in vitro in isolated tissues and organs collected from these rats. The protocol will examine the effects of acute single dose as well as chronic 4 or 16 week administration of L- and D-arginine. Two oral doses will be chosen from the lower and higher ends of the dose range reported in the literature. The long-term goal of my research program is to investigate the impact of these amino acids on carbohydrate and fatty acid metabolic pathways and on the molecular mechanisms of MG and AGEs generation, initially in animals (rats) and subsequently in human. Other amino acids of interest in my research program are cysteine and lysine, due to their great affinity for MG, and possible impact on the physiology of MG and AGEs formation. OUTCOME: The results of my study will help to advance the knowledge on the physiological impact of oral L- and D-arginine, and other amino acids, and establish their metabolic fate in animals and humans. A beneficial interaction of arginine and cysteine with physiological processes of MG and AGEs formation may possibly encourage research examining fortification of normal diets with the amino acids studied.