Vitamin C (ascorbic acid) physiology

维生素 C（抗坏血酸）生理学

• 批准号: 8939613
• 负责人: MARK A LEVINE
• 金额: $ 24.99万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8939613
• 关键词: Adrenal Glands; Adrenal hormone preparation; Affect; Animals; Ascorbic Acid; Biochemistry; Blood specimen; Catheters; Cell physiology; Clinical; Corticotropin; Data; Diabetes Mellitus; Diagnostic; Diet; Disease; Drug Kinetics; Eating; Erythrocytes; Evaluation; Fasting; Food; Foundations; Health; Hormones; Human; Hydrocortisone; Hyperaldosteronism; Ingestion; Intake; Measures; Mediating; Methods; Modeling; Molecular Biology; Patients; Peripheral; Physiology; Plasma; Recommendation; Sampling; Techniques; Testing; Tissues; Veins; Vitamins; Work; biological adaptation to stress; fruits and vegetables; paracrine; peripheral blood

Summary Rather than deficiency models, a concentration-function approach is a more rational approach to determine vitamin intake recommendations for humans. Vitamin C is used as a model vitamin for this work. A concentration-function approach is critically dependent on understanding vitamin C biochemistry and molecular biology; vitamin C clinical pharmacokinetics; and vitamin C physiology. To study concentration-function and physiology relationships in humans for vitamin C, it is necessary to choose clinical samples that can be obtained easily; that contain the vitamin; and where changes in vitamin C concentration may affect physiology and/or cell function. For these reasons, we focused on human red blood cells. As a prerequisite, we developed a new method to measure vitamin C in human red blood cells. This method is the foundation for exploring new functions of vitamin C in red blood cells in health and disease with focus on diabetes. Humans, unlike most animals, cannot synthesize vitamin C and instead must obtain it from diet. Healthy humans who eat at least 5 servings of fruits and vegetables daily will obtain 200 mg or more of vitamin C. This will produce steady-state fasting plasma concentrations of 70 -80 umoles per liter. Ingestion of more vitamin C from foods will not produce higher concentrations. Even if a vitamin C supplement is taken, plasma concentrations will only rise transiently. All tissues, except red cells, accumulate vitamin C against its plasma concentration. However, once plasma concentrations reach 50 to 60 umoles per liter, tissue concentrations are saturated and do not rise further. Thus, vitamin C concentrations are tightly controlled. Why tight control occurs is unknown. We postulated that one explanation is that tight control of plasma concentrations could facilitate paracrine, or local, actions of the vitamin, if such concentrations were higher. To test this hypothesis, we investigated whether paracrine secretion of vitamin C occurs from adrenal glands in humans. As part of the diagnostic evaluation of patients with hyperaldosteronism, we administered adrenocorticotrophic hormone intravenously to 26 patients. Under radiographic guidance, catheters were placed in both adrenal veins, and adrenal and peripheral blood samples were taken after adrenocorticotrophic hormone was administered. Vitamin C and cortisol concentrations were measured in 47 adrenal veins and 26 peripheral veins. Following adrenocorticotrophic hormone, adrenal vein vitamin C concentrations increased in all cases. The mean peak value increased to 176 +/- 71 umoles per liter, reached between 1 and 4 minutes after adrenocorticotrophic hormone, while peripheral values were unchanged at 35 +/- 15 umoles per liter. Adrenal vein vitamin C concentrations declined nearly to baseline 15 minutes after adrenocorticotrophic hormone. In all cases, adrenal vein vitamin C release preceded cortisol release. The findings were statistically significant with p values for differences < 0.0001. These data are the first description in any species of simultaneous adrenal vein peripheral vitamin C concentrations before and after ACTH stimulation; are the first demonstration that the function of secreted vitamin C must be local rather than systemic; and are the first example of hormone mediated secretion of any vitamin in humans. The data indicate that adrenal vitamin C release in humans is an integral part of the stress response. The data validate the hypothesis that one reason for tight control of vitamin C concentrations is to facilitate a paracrine function. The function of secreted vitamin C in adrenals is unknown, and will be the subject of future research.

总结 与缺乏模型相比，浓度函数方法是确定人类维生素摄入量建议的更合理方法。维生素C被用作这项工作的模型维生素。浓度-功能方法在很大程度上依赖于对维生素C生物化学和分子生物学、维生素C临床药代动力学和维生素C生理学的理解。 为了研究人体中维生素C的浓度-功能和生理学关系，有必要选择容易获得的临床样品;含有维生素;维生素C浓度的变化可能影响生理学和/或细胞功能。 基于这些原因，我们专注于人类红细胞。作为先决条件，我们开发了一种新的方法来测量人体红细胞中的维生素C。该方法是探索红细胞中维生素C在健康和疾病中的新功能的基础，重点是糖尿病。 与大多数动物不同，人类不能合成维生素C，而是必须从饮食中获得。健康的人每天至少吃5份水果和蔬菜，将获得200毫克或更多的维生素C。这将产生70 - 80 μ mol/L的稳态空腹血浆浓度。从食物中摄入更多的维生素C不会产生更高的浓度。即使服用维生素C补充剂，血浆浓度也只会短暂升高。除红细胞外，所有组织都积累维生素C，而不是血浆浓度。然而，一旦血浆浓度达到每升50至60微摩尔，组织浓度就饱和了，不再进一步上升。因此，维生素C浓度受到严格控制。 为什么会出现严格控制尚不清楚。我们假设，一种解释是，严格控制血浆浓度可以促进旁分泌，或局部，维生素的作用，如果这样的浓度较高。 为了验证这一假设，我们研究了人体肾上腺是否存在维生素C的旁分泌。作为醛固酮增多症患者诊断评估的一部分，我们对26例患者静脉注射促肾上腺皮质激素。在影像学引导下，将导管置于双侧肾上腺静脉，并在给予促肾上腺皮质激素后采集肾上腺和外周血样本。测量了47条肾上腺静脉和26条外周静脉中的维生素C和皮质醇浓度。 促肾上腺皮质激素后，所有病例肾上腺静脉维生素C浓度均升高。平均峰值增加到176 +/- 71微摩尔/升，在促肾上腺皮质激素后1 - 4分钟达到，而外周值不变，为35 +/- 15微摩尔/升。注射促肾上腺皮质激素后15分钟，肾上腺静脉维生素C浓度下降至接近基线水平。在所有情况下，肾上腺静脉维生素C的释放先于皮质醇的释放。结果具有统计学显著性，差异p值< 0.0001。 这些数据是第一次描述在任何物种的肾上腺静脉外周维生素C浓度的同时促肾上腺皮质激素刺激前后;是第一次证明分泌的维生素C的功能必须是局部的，而不是全身的;是第一个例子激素介导的分泌任何维生素在人类。这些数据表明，人体肾上腺释放维生素C是应激反应的一个组成部分。这些数据验证了严格控制维生素C浓度的一个原因是促进旁分泌功能的假设。肾上腺分泌维生素C的功能尚不清楚，这将是未来研究的主题。