Therapeutic and Metabolic Responses of Citrulline vs. Arginine Supplementation

瓜氨酸与精氨酸补充剂的治疗和代谢反应

• 批准号: 8754042
• 负责人: Juan Marini
• 金额: $ 26.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8754042
• 关键词: Accounting; Address; Adverse effects; Arginine; Arginine deiminase; Blood Circulation; Blood Pressure; Cancer Patient; Cell Proliferation; Cells; Chronic; Citrulline; Creatine; Drug Kinetics; Energy Metabolism; Enzymes; Goals; Hemolysis; Homeostasis; Human; Hydrolysis; Hypertension; Immune response; In Situ; Inflammatory Bowel Diseases; Kidney; Knowledge; Liver; Measures; Metabolic; Metabolism; Molecular; Mus; Nitric Oxide; Outcome; Peripheral; Physiological; Plasma; Polyamines; Pre-Eclampsia; Process; Production; Protein Biosynthesis; Proteinuria; Recommendation; Relative (related person); Reporting; Role; Safety; Sepsis; Sickle Cell Anemia; Site; Source; Supplementation; Telemetry; Therapeutic; Therapy Clinical Trials; Tissues; Trauma; arginase; base; blood pressure regulation; cell type; conditionally essential amino acid; experience; improved; liver metabolism; meetings; mouse model; oxidation; public health relevance; response; stable isotope; therapeutic development

DESCRIPTION (provided by applicant): Arginine is a conditionally essential amino acid that has many functional roles besides protein synthesis. Arginine is utilized for the synthesis of creatine, polyamines and nitric oxide and thus has a central role in energy metabolism, cell proliferation and in the regulation of blood pressure and immune response. Arginine supplementation has been beneficial in a variety of circumstances such as preeclampsia, hypertension, and sepsis. Detrimental outcomes, however, have been reported, and the long term safety and efficacy of arginine therapy remain poorly described. Citrulline, the precursor for endogenous arginine synthesis, is a viable alternative to arginine supplementation. Whereas first pass extraction and hydrolysis of arginine is considerable (~40%, and likely to increase due to supplementation) citrulline escapes liver metabolism. For this reason citrulline supplementation has the potential to deliver more arginine to peripheral tissues than arginine supplementation itself. Moreover, different cell types have the ability to directly utilize citrullne to meet their local arginine needs. This ability of cells to directly utilize citrulline is the reasonwhy cancer patients treated with pegylated arginine deiminase (ADI-PEG), which results in arginine depletion but high levels of citrulline, are able to maintain metabolic homeostasis. Citrulline supplementation has the added advantage that it can provide arginine when arginine availability is compromised due to high arginase activity in the gut and circulation (e.g., inflammatory bowel disease, sickle cell anemia hemolysis). To address the hypothesis that supplemental citrulline is a better source of endogenous arginine availability than arginine supplementation itself, we propose the following specific aims. Specific Aim 1: To determine the pharmacokinetics, oxidation and the first pass metabolism of arginine when arginine or citrulline are chronically supplemented in mice. Specific Aim 2: To determine the molecular basis for increased citrulline utilization when arginine is limiting and to determine fractional protein synthesis rate of differet tissues, whole body nitric oxide production and blood pressure in ADI-PEG arginine-depleted mice. Specific Aim 3: To determine the reduction in blood pressure in a chronic hypertensive mouse model and in a mouse model of preeclampsia supplemented with different levels of arginine and citrulline. Different metabolic (fluxes, oxidation, metabolite interconversion) and physiological (blood pressure, NO synthesis, protein synthesis) endpoints will be measured utilizing stable isotopes and blood pressure telemetry. Our current knowledge can only account for ~60% of the citrulline produced as the precursor for plasma arginine. Because the only known fate of citrulline is its conversion into arginine the unaccounted citrulline is likely to provide the precursor for local arginine synthesis. These studies will fill the gap in our knowledge regarding this unaccounted citrulline and its physiological effect. Moreover this information will provide the basis for new human therapeutic trials and recommendations on arginine and citrulline supplementation when the demand for arginine is increased as in hypertension, preeclampsia, sepsis, inflammatory bowel disease, and sickle cell anemia.

描述（由申请人提供）：精氨酸是一种条件性必需氨基酸，除蛋白质合成外还具有许多功能作用。精氨酸用于肌酸、多胺和一氧化氮的合成，因此在能量代谢、细胞增殖以及血压和免疫反应的调节中具有核心作用。精氨酸补充剂在多种情况下是有益的，例如先兆子痫、高血压和败血症。然而，已经报道了不利的结果，并且精氨酸治疗的长期安全性和有效性仍然缺乏描述。瓜氨酸， 内源性精氨酸合成是精氨酸补充的可行替代方案。虽然精氨酸的首过提取和水解相当可观（约40%，并且可能由于补充而增加），但瓜氨酸逃脱肝脏代谢。因此，瓜氨酸补充剂比精氨酸补充剂本身有可能向外周组织输送更多的精氨酸。此外，不同的细胞类型有能力直接利用瓜氨酸来满足其局部精氨酸需求。这种细胞直接利用瓜氨酸的能力是为什么用聚乙二醇化精氨酸脱亚胺酶（ADI-PEG）治疗的癌症患者能够维持代谢稳态的原因，ADI-PEG导致精氨酸耗尽，但瓜氨酸水平高。瓜氨酸补充剂具有额外的优点，即当精氨酸的可用性由于肠道和循环中的高精氨酸酶活性而受到损害时，它可以提供精氨酸（例如，炎症性肠病、镰状细胞性贫血溶血）。为了解决补充瓜氨酸是比补充精氨酸本身更好的内源性精氨酸可用性来源的假设，我们提出了以下具体目标。具体目标1：确定小鼠长期补充精氨酸或瓜氨酸时精氨酸的药代动力学、氧化和首过代谢。具体目标二：确定精氨酸受限时瓜氨酸利用率增加的分子基础，并确定ADI-PEG精氨酸耗竭小鼠的肾脏组织蛋白质合成率、全身一氧化氮生成量和血压。具体目标3：确定补充不同水平精氨酸和瓜氨酸的慢性高血压小鼠模型和先兆子痫小鼠模型的血压降低情况。将利用稳定同位素和血压遥测测量不同的代谢（通量、氧化、代谢物互变）和生理（血压、NO合成、蛋白质合成）终点。我们目前的知识只能解释约60%的瓜氨酸作为血浆精氨酸的前体产生。由于瓜氨酸的唯一已知命运是转化为精氨酸，因此未说明的瓜氨酸可能为局部精氨酸合成提供前体。这些研究将填补我们对瓜氨酸及其生理作用的认识上的差距。此外，当精氨酸需求增加时，如高血压、先兆子痫、败血症、炎症性肠病和镰状细胞贫血，这些信息将为新的人体治疗试验和精氨酸和瓜氨酸补充剂的建议提供基础。