L-Citrulline: A Non-Essential Amino Acid with Important Roles in Human Health
Source abstract
Abstract
L-Arginine (Arg) has been widely used due to its functional properties as a substrate for nitric oxide (NO) generation. However, L-citrulline (CIT), whose main natural source is watermelon, is a non-essential amino acid but which has important health potential. This review provides a comprehensive approach to different studies of the endogenous synthesis of CIT, metabolism, pharmacokinetics, and pharmacodynamics as well as its ergogenic effect in exercise performance. The novel aspect of this paper focuses on the different effects of CIT, citrulline malate and CIT from natural sources such as watermelon on several topics, including cardiovascular diseases, diabetes, erectile dysfunction, cancer, and exercise performance. CIT from watermelon could be a natural food-sourced substitute for pharmacological products and therefore the consumption of this fruit is promoted.
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Research context
OpenAlex topics: Nitric Oxide and Endothelin Effects · Electrochemical sensors and biosensors · Analytical Chemistry and Sensors
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Food Quality and Health Group, Campus Muralla del Mar, Institute of Plant Biotechnology, Universidad Politécnica de Cartagena (UPCT), 30202 Cartagena, Spain
Postharvest and Refrigeration Group, Escuela Técnica Superior de Ingeniería Agronómica (ETSIA), UPCT, Paseo Alfonso XIII, 48, 30203 Cartagena, Spain
Department of Education, Health Research Center, University of Almería, Carretera Sacramento s/n, 04120 Almería, La Cañada de San Urbano, Spain
References (100+)
Show source-provided references
1. The Effect of Nitric-Oxide-Related Supplements on Human Performance10.2165/11596860-000000000-00000 ↗
2. Elevated plasma citrulline and arginine due to consumption of Citrullus vulgaris (watermelon)10.1007/s10545-005-0467-1 ↗
3. Source and fate of circulating citrulline10.1152/ajpendo.1981.241.6.E473 ↗
4. Determination of citrulline in watermelon rind10.1016/j.chroma.2005.05.009 ↗
5. Bio-active compounds of different cultivars from flesh and by-product of fresh-cut watermelons10.1002/jsfa.4250 ↗
6. Systematized biosynthesis and catabolism regulate citrulline accumulation in watermelon10.1016/j.phytochem.2019.03.003 ↗
7. Aguayo, E., and Tarazona-Díaz, M.P. (2020, November 12). National Patent: Procedimiento Para la Obtención de un Extracto de L-Citrulina a Partir de Plantas Cucurbitáceas. ES2394250 A1. Available online: http://www.oepm.es/pdf/ES/0000/000/02/39/42/ES-2394250_A1.pdf.
8. FAOSTAT Agriculture Data (2020, November 12). Available online: http://www.fao.org/faostat/en/#data/QC/visualize.
9. FAO (2020, November 15). Fruit and Vegetables–Your Dietary Essentials. The International Year of Fruits and Vegetables, 2021, Background Paper. Rome. Available online: http://www.fao.org/documents/card/en/c/cb2395en.
10. Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction10.1016/j.clnu.2008.02.005 ↗
11. Arginine metabolism: Nitric oxide and beyond10.1042/bj3360001 ↗
12. Citrulline and nitrogen homeostasis: An overview10.1007/s00726-015-1932-2 ↗
13. Citrulline: From metabolism to therapeutic use10.1016/j.nut.2012.07.002 ↗
14. Plasma Arginine and Ornithine Are the Main Citrulline Precursors in Mice Infused with Arginine-Free Diets10.3945/jn.110.125377 ↗
15. Arginine Can Be Synthesized from Enteral Proline in Healthy Adult Humans10.3945/jn.110.137224 ↗
16. Intestinal Mucosal Amino Acid Catabolism10.1093/jn/128.8.1249 ↗
17. Plasma citrulline level as a biomarker for cancer therapy-induced small bowel mucosal damage
18. Almost all about citrulline in mammals10.1007/s00726-005-0235-4 ↗
19. Arginine de novo and nitric oxide production in disease states10.1152/ajpendo.00284.2012 ↗
20. Morris, S.M. (2020). Regulation of arginine availability and its impact on NO synthesis. Nitric Oxide: Biology and Pathobiology, Academic Press.
21. Renal metabolism of amino acids: Its role in interorgan amino acid exchange10.1093/ajcn/79.2.185 ↗
22. Arginine Metabolic Enzymes, Nitric Oxide and Infection10.1093/jn/134.10.2820S ↗
23. Arginase: A Critical Regulator of Nitric Oxide Synthesis and Vascular Function10.1111/j.1440-1681.2007.04638.x ↗
24. Arginase as a potential target in the treatment of cardiovascular disease: Reversal of arginine steal?10.1093/cvr/cvt036 ↗
25. Endothelial dysfunction and vascular disease-A 30th anniversary update10.1111/apha.12646 ↗
26. L-arginine-induced vasodilation in healthy humans: Pharmacokinetic-pharmacodynamic relationship10.1046/j.1365-2125.1998.00803.x ↗
27. Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle10.1046/j.1432-1033.2003.03559.x ↗
28. Nitric oxide synthases: Regulation and function10.1093/eurheartj/ehr304 ↗
29. Oral L-citrulline supplementation enhances cycling time trial performance in healthy trained men: Double-blind randomized placebo-controlled 2-way crossover study10.1186/s12970-016-0117-z ↗
30. Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability10.1016/j.bbrc.2014.10.029 ↗
31. Regulation of nitric oxide production in health and disease10.1097/MCO.0b013e328332f99d ↗
32. Plasma Asymmetric Dimethylarginine and Incidence of Cardiovascular Disease and Death in the Community10.1161/CIRCULATIONAHA.108.838268 ↗
33. Citrulline: Pharmacological perspectives and its role as an emerging biomarker in future10.1111/j.1472-8206.2012.01059.x ↗
34. Leucine and citrulline: Two major regulators of protein turnover
35. Effects of leucine and citrulline versus non-essential amino acids on muscle protein synthesis in fasted rat: A common activation pathway?10.1007/s00726-011-1172-z ↗
36. Leucine and citrulline modulate muscle function in malnourished aged rats10.1007/s00726-011-0841-2 ↗
37. Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet–A pilot study10.1016/j.clnu.2014.04.019 ↗
38. Synergistic effects of citrulline supplementation and exercise on performance in male rats: Evidence for implication of protein and energy metabolisms10.1042/CS20170088 ↗
39. Effect of citrulline on muscle functions during moderate dietary restriction in healthy adult rats10.1007/s00726-013-1564-3 ↗
40. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: The Citrudose pharmacokinetic study10.1017/S0007114507841110 ↗
41. Therapeutic Use of Citrulline in Cardiovascular Disease. Cardiovasc
42. Manipulation of citrulline availability in humans10.1152/ajpgi.00289.2007 ↗
43. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: Impact on nitric oxide metabolism10.1111/j.1365-2125.2007.02990.x ↗
44. Arginine behaviour after arginine or citrulline administration in older subjects10.1017/S0007114515004638 ↗
45. Plasma Membrane Transporters for Arginine10.1093/jn/134.10.2752S ↗
46. Characteristics of L-Citrulline Transport across Rat Small Intestine In Vitro10.1203/00006450-199210000-00019 ↗
47. Allerton, T.D., Proctor, D.N., Stephens, J.M., Dugas, T.R., Spielmann, G., and Irving, B.A. (2018). L-Citrulline Supplementation: Impact on Cardiometabolic Health. Nutrients, 10.10.3390/nu10070921 ↗
48. Adverse Gastrointestinal Effects of Arginine and Related Amino Acids10.1093/jn/137.6.1693S ↗
49. Watermelon consumption increases plasma arginine concentrations in adults
50. Oral citrulline does not affect whole body protein metabolism in healthy human volunteers: Results of a prospective, randomized, double-blind, cross-over study10.1016/j.clnu.2011.06.005 ↗
51. The effect of L-citrulline and watermelon juice supplementation on anaerobic and aerobic exercise performance10.1080/02640414.2014.990495 ↗
52. l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans10.1152/japplphysiol.00192.2014 ↗
53. Consumption of Watermelon Juice Enriched in l -Citrulline and Pomegranate Ellagitannins Enhanced Metabolism during Physical Exercise10.1021/acs.jafc.7b00586 ↗
54. Biochemical, physiological, and performance response of a functional watermelon juice enriched in L-citrulline during a half-marathon race10.1080/16546628.2017.1330098 ↗
55. Buckinx, F., Gouspillou, G., Carvalho, L.P., Marcangeli, V., Boutros, G.E.H., Dulac, M., Noirez, P., Morais, J.A., Gaudreau, P., and Aubertin-Leheudre, M. (2018). Effect of High-Intensity Interval Training Combined with L-Citrulline Supplementation on Functional Capacities and Muscle Function in Dynapenic-Obese Older Adults. J. Clin. Med., 7.10.3390/jcm7120561 ↗
56. One Week of L-Citrulline Supplementation Improves Performance in Trained Cyclists10.1519/JSC.0000000000003418 ↗
57. Impact of l-citrulline supplementation on oxygen uptake kinetics during walking10.1139/apnm-2017-0696 ↗
58. Diabetes-induced Coronary Vascular Dysfunction Involves Increased Arginase Activity10.1161/CIRCRESAHA.107.155028 ↗
59. Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis10.1186/s12970-015-0086-7 ↗
60. l-Citrulline-malate influence over branched chain amino acid utilization during exercise10.1007/s00421-010-1509-4 ↗
61. Effects of citrulline supplementation on fatigue and exercise performance in mice10.3177/jnsv.57.246 ↗
62. Doesl-citrulline supplementation improve exercise blood flow in older adults?10.1113/EP086587 ↗
63. Effect of arginine, omithine and citrulline supplementation upon performance and metabolism of trained rats10.1002/cbf.1000 ↗
64. Spinal and Supraspinal Factors in Human Muscle Fatigue10.1152/physrev.2001.81.4.1725 ↗
65. Branched-Chain Amino Acids and Central Fatigue10.1093/jn/136.1.274S ↗
66. Branched-Chain Amino Acids and Brain Function10.1093/jn/135.6.1539S ↗
67. Stimulation of muscle ammonia production during exercise following branched-chain amino acid supplementation in humans10.1113/jphysiol.1996.sp021433 ↗
68. Cerebral ammonia uptake and accumulation during prolonged exercise in humans10.1113/jphysiol.2004.075838 ↗
69. Ammonia metabolism, the brain and fatigue; revisiting the link10.1016/j.pneurobio.2010.01.012 ↗
70. Chang, C.-K., Chien, K.-M.C., Chang, J.-H., Huang, M.-H., Liang, Y.-C., and Liu, T.-H. (2015). Branched-Chain Amino Acids and Arginine Improve Performance in Two Consecutive Days of Simulated Handball Games in Male and Female Athletes: A Randomized Trial. PLoS ONE, 10.10.1371/journal.pone.0121866 ↗
71. Branched-chain amino acids, arginine, citrulline alleviate central fatigue after 3 simulated matches in taekwondo athletes: A randomized controlled trial10.1186/s12970-016-0140-0 ↗
72. Citrulline Malate Enhances Athletic Anaerobic Performance and Relieves Muscle Soreness10.1519/JSC.0b013e3181cb28e0 ↗
73. Citrulline/malate promotes aerobic energy production in human exercising muscle10.1136/bjsm.36.4.282 ↗
74. Influence of L-citrulline and watermelon supplementation on vascular function and exercise performance10.1097/MCO.0000000000000340 ↗
75. Acute citrulline malate supplementation improves upper- and lower-body submaximal weightlifting exercise performance in resistance-trained females10.1007/s00394-015-1124-6 ↗
76. The Effect of Citrulline/Malate on Blood Lactate Levels in Intensive Exercise10.1007/s10528-017-9807-8 ↗
77. Modification of fatigue indicators using citrulline malate for high performance endurance athletes
78. Citrulline malate supplementation increases muscle efficiency in rat skeletal muscle10.1016/j.ejphar.2011.05.068 ↗
79. Effects of Supplemental Citrulline Malate Ingestion During Repeated Bouts of Lower-Body Exercise in Advanced Weightlifters10.1519/JSC.0000000000000670 ↗
80. Acute Citrulline-Malate Supplementation and High-Intensity Cycling Performance10.1519/JSC.0000000000001338 ↗
81. Da Silva, D.K., Jacinto, J.L., de Andrade, W.B., Roveratti, M.C., Estoche, J.M., Balvedi, M.C.W., de Oliveira, D.B., da Silva, R.A., and Aguiar, A.F. (2017). Citrulline malate does not improve muscle recovery after resistance exercise in untrained young adult men. Nutrients, 9.10.3390/nu9101132 ↗
82. Citrulline malate supplementation might potentiate post-exercise hypotension in hypertensives: A 24-hour analysis10.1016/j.scispo.2019.03.001 ↗
83. Endothelial Dysfunction as a Target for Prevention of Cardiovascular Disease10.2337/dc09-S330 ↗
84. Sharifi-Rad, J., Rodrigues, C.F., Sharopov, F., Docea, A.O., Can Karaca, A., Sharifi-Rad, M., Kahveci Karıncaoglu, D., Gülseren, G., Şenol, E., and Demircan, E. (2020). Diet, Lifestyle and Cardiovascular Diseases: Linking Pathophysiology to Cardioprotective Effects of Natural Bioactive Compounds. Int. J. Environ. Res. Public Health, 17.10.3390/ijerph17072326 ↗
85. Effect of chronic nitrate and citrulline supplementation on vascular function and exercise performance in older individuals10.18632/aging.101984 ↗
86. Khalaf, D., Krüger, M., Wehland, M., Infanger, M., and Grimm, D. (2019). The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure. Nutrients, 11.10.3390/nu11071679 ↗
87. L-citrulline and L-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits10.1073/pnas.0506595102 ↗
88. Effects of Oral L-Citrulline Supplementation on Lipoprotein Oxidation and Endothelial Dysfunction in Humans with Vasospastic Angina10.2174/18715222113139990008 ↗
89. Acute ingestion of citrulline stimulates nitric oxide synthesis but does not increase blood flow in healthy young and older adults with heart failure
90. Chronic l-citrulline supplementation improves cardiac sympathovagal balance in obese postmenopausal women: A preliminary report10.1016/j.autneu.2016.06.005 ↗
91. Arginase inhibition alleviates hypertension associated with diabetes: Effect on endothelial dependent relaxation and NO production10.1016/j.vph.2012.01.001 ↗
92. Tsuboi, T., Maeda, M., and Hayashi, T. (2018). Administration of L-arginine plus L-citrulline or L-citrulline alone successfully retarded endothelial senescence. PLoS ONE, 13.10.1371/journal.pone.0192252 ↗
93. Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats10.1093/jn/137.12.2680 ↗
94. Arginase inhibition improves microvascular endothelial function in patients with type 2 diabetes mellitus10.1210/jc.2016-2007 ↗
95. Arginase inhibition alleviates hypertension in the metabolic syndrome10.1111/bph.12144 ↗
96. Citrulline Supplementation Improves Organ Perfusion and Arginine Availability under Conditions with Enhanced Arginase Activity10.3390/nu7075217 ↗
97. Diabetic nephropathy is resistant to oral l-arginine or l-citrulline supplementation10.1152/ajprenal.00176.2014 ↗
98. Potential roles of Citrulline and watermelon extract on metabolic and inflammatory variables in diabetes mellitus, current evidence and future directions: A systematic review10.1111/1440-1681.13190 ↗
99. Oral L-Citrulline Supplementation Improves Erection Hardness in Men With Mild Erectile Dysfunction10.1016/j.urology.2010.08.028 ↗
100. Levels of l -arginine and l -citrulline in patients with erectile dysfunction of different etiology10.1111/andr.12293 ↗