Arginine

Common Name: Arginine

Clinical Name: L-Arginine

Summary

L-Arginine

overview of interactions:
• nutrient affecting drug toxicity: Cyclosporine

chemistry/function: Arginine is a complex amino acid that is often found at the active (or catalytic) site in proteins and enzymes due to its amine-containing side chain. Arginine's primary function is the transport, storage, and excretion of nitrogen. The majority of arginine is used in urea metabolism. Arginine is involved with immunity and also in maintaining body weight during acute trauma. While arginine is often considered an essential amino acid which must be obtained through the diet, this is true only during the juvenile period in humans; thereafter, it can also made in the body from ornithine.

dietary sources: Walnuts, filberts, pecans, Brazil nuts, sesame and sunflower seeds, brown rice, raisins, coconut, gelatin, buckwheat, almonds, barley, cashews, cereals, chicken, chocolate, corn, dairy products, meats, oats, and peanuts.

deficiency:
• Usually related to overall protein malnutrition, an arginine deficiency can occur with excessive ammonia production or with protein or enzyme deficiency.
• Arginine deficiency is associated with rash, hair loss, poor wound healing, constipation, fatty liver, and cirrhosis.

known or potential therapeutic uses: Angina, burns, congestive heart failure, cystic fibrosis, enhancing formation of muscle mass, gastritis, hypercholesterolemia, infertility from oligospermia, inflammatory bowel disease, immunity enhancement, trauma, wound healing enhancement.

maintenance dose: Usually not necessary. Optimal levels of intake have not been established.

therapeutic dose: Researchers and practitioners of natural medicine have used a wide range of dosages, from 2-30 grams per day, with 6 g per day being representative for most conditions. Long term use is usually not advisable.

toxicity: Excessive arginine (greater than 40 g per day) can cause diarrhea. Hyperphosphatemia can be induced by arginine in patients with severe hepatic disease and kidney problems. Despite numerous studies demonstrating the immune enhancing activity of arginine, including research with breast cancer, some researchers have suggested that high doses of arginine can increase the growth of cancer cells in humans.
(Brittenden J, et al. Surgery. 1994 Feb;115(2):205-212; Park KGM. Proc Nutr Soc 1993;52:387-401.)

contraindications: Herpes simplex, kidney disease.



Interactions

nutrient affecting drug toxicity: Cyclosporine

• research: Studies involving rats indicate that oral supplementation of L-arginine can prevent chronic cyclosporine nephrotoxicity.
(Yang CW, et al. Exp Nephrol 1998 Jan;6(1):50-56; Alexander JW, et al. JPEN J Parenter Enteral Nutr 1998 May;22(3):152-155; Andoh TF, et al. Transplantation 1997 Nov 15;64(9):1236-1240; Assis SM, et al. Transplantation 1997 Apr 27;63(8):1070-1073.)

• mechanism: Nitric oxide (NO) decreases cyclosporine nephrotoxicity and arginine is a nitric oxide substrate. Nitric oxide can also have both effector (cytotoxic) and regulatory roles in immune function.

• nutritional support: Given the preliminary state of the research involved, supplementation with L-arginine cannot be suggested as offering definite benefit. However, other research with animals indicates that arginine may inhibit tumor growth by activating macrophage cytotoxic effects.
(Marcinkiewicz J, et al. Eur J Immunol 1995 Apr;25(4):947-951.)

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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

Alexander JW, Levy A, Custer D, Valente JF, Babcock G, Ogle CK, Schroeder TJ. Arginine, fish oil, and donor-specific transfusions independently improve cardiac allograft survival in rats given subtherapeutic doses of cyclosporin. JPEN J Parenter Enteral Nutr 1998 May;22(3):152-155.

Andoh TF, Gardner MP, Bennett WM. Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity. Transplantation 1997 Nov 15;64(9):1236-1240.

Assis SM, Monteiro JL, Seguro AC. L-Arginine and allopurinol protect against cyclosporine nephrotoxicity. Transplantation 1997 Apr 27;63(8):1070-1073.
Abstract: The role of nitric oxide (NO) and oxygen free radicals in cyclosporine (CsA) nephrotoxicity was investigated using L-arginine, an NO substrate, and allopurinol, a xanthine oxidase inhibitor (involved in the formation of oxygen radicals) in an experimental model with Wistar rats. CsA, administered at 15 mg/kg/body weight (BW) subcutaneously for 10 days, caused a decrease in glomerular filtration rate, with inulin clearance of 0.33+/-0.04 vs. 1.11+/-0.06 ml/min/100 g BW (P<0.01 vs. control). L-Arginine, 1.5% in drinking water 5 days before and during CsA administration, partially protected the animals against this fall in glomerular filtration rate, with inulin clearance of 0.68+/-0.03 ml/min/100 g BW (P<0.01 vs. CsA). Allopurinol, at 10 mg/kg/BW by gavage, also had a protective action, with inulin clearance of 0.54+/-0.04 ml/min/100 g (P<0.01 vs. CsA). CsA caused an elevation in NO production, as assessed by urinary excretion of its metabolites, nitrite and nitrate (NO2 and NO3; 0.836+/-0.358 vs. 0.107+/-0.019 nmol/microg creatinine). NO production was as much as threefold higher in the L-arginine group (1.853+/-0.206 nmol/g creatinine). This CsA effect is probably related to its vasoconstrictive stimulus. Supplementation with L-arginine, which provides more substrate for NO formation, may enhance vasodilatation and consequently reduce the impairment of renal function. The protection provided by allopurinol may be related to the reduced formation of oxygen radicals, preventing the deleterious effects of lipid peroxidation.

Brittenden J, Heys SD, Ross J, Park KG, Eremin O. Natural cytotoxicity in breast cancer patients receiving neoadjuvant chemotherapy: effects of L-arginine supplementation. Eur J Surg Oncol. 1994 Aug;20(4):467-472.
Abstract: Certain cytotoxic drugs have been shown to suppress host anti-cancer defence mechanisms. The amino acid L-arginine can significantly enhance natural killer (NK) and lymphokine-activated killer (LAK) cell cytotoxicity in patients with locally advanced breast cancer. In this study, the effect of L-arginine supplementation on natural cytotoxicity was determined in patients with breast cancer receiving CHOP chemotherapy. This cytotoxic regimen caused a transient immunosuppression, maximal on day 14 of each cycle (P < 0.001); this was not cumulative during the four cycles of treatment. Those patients receiving L-arginine supplementation (30 g/day for 3 days prior to each course of chemotherapy) had a smaller and delayed onset of immunosuppression (day 14), compared with those patients who had CHOP only (day 9). L-Arginine was able to repeatedly stimulate NK and LAK cell cytotoxicity in patients who were receiving CHOP chemotherapy (P < 0.003). In conclusion, further studies are required to determine the optimal use of chemotherapeutic agents, alone or in combination with immunostimulators, to avoid inhibition of host anti-cancer defence mechanisms.

Brittenden J, Park KG, Heys SD, Ross C, Ashby J, Ah-See Ak, Eremin O.  L-arginine stimulates host defenses in patients with breast cancer. Surgery. 1994 Feb;115(2):205-212.
Abstract: BACKGROUND. The amino acid L-arginine is known to have immunostimulatory effects in animals and healthy human volunteers. We have studied the effect of dietary supplementation with L-arginine (30 gm/day for 3 days) on host defenses in patients with breast cancer. METHODS. Mitogenic responses of peripheral blood lymphocytes to concanavalin A, phytohemagglutinin, and pokeweed mitogen and phenotype analysis of lymphocyte subsets and activation markers were assessed before and after 3 days of L-arginine supplementation. The effect of L-arginine supplementation on natural killer and lymphokine-activated killer cell cytotoxicity and serum levels of the cytokines interleukin-1 beta and 2, interferon-gamma, and tumor necrosis factor-alpha were also measured. RESULTS. L-arginine significantly increased lymphocyte mitogenic reactivity to concanavalin A, phytohemagglutinin, and pokeweed mitogen (mean percentage increases: 64% [p < 0.001], 65% [p < 0.001], and 48% [p < 0.05], respectively). Natural killer and lymphokine-activated killer cell cytotoxicity was also significantly enhanced after L-arginine intake (mean percentage increase, 81% and 107% [p < 0.001]). However, no corresponding increase in circulating CD16+ and CD56+ cells was obtained: Arginine supplementation did not increase the level of serum cytokines. CONCLUSIONS. Dietary supplementation with L-arginine in patients with breast cancer significantly enhances host defenses and therefore may have a role in adjuvant treatment.

Brittenden J, Heys SD, Ross J, Park KG, Eremin O. Nutritional pharmacology: effects of L-arginine on host defences, response to trauma and tumour growth. Clin Sci (Colch). 1994 Feb;86(2):123-132.

Gennari R, Alexander JW. Arginine, glutamine, and dehydroepiandrosterone reverse the immunosuppressive effect of prednisone during gut-derived sepsis. Crit Care Med 1997 Jul;25(7):1207-1214.
Abstract: OBJECTIVE: Corticosteroids are used broadly in clinical practice but may profoundly impair resistance to infections. In contrast, arginine and glutamine are safe and effective immunonutrients that can improve resistance to infection in both animals and humans. This study assessed whether arginine and/or glutamine, with or without dehydroepiandrosterone, a natural endogenous steroid, could reverse the susceptibility to infection caused by prednisone in a burned animal model. DESIGN: Prospective, randomized study. SETTING: A laboratory approved by the American Association for the Accreditation of Laboratory Animal Care at the Shriners Burns Institute, Cincinnati Unit. SUBJECTS: Adult female Balb/c mice, weighing 18 to 22 g. INTERVENTIONS: Animals were prefed an arginine- and/or glutamine- or a glycine-supplemented diet for 14 days. Dehydroepiandrosterone (25 mg/kg/day) and/or prednisone (10 mg/kg/day) were given on days -4 to 0 before animals were given a gavage of 10(9) 111indium-oxine-radiolabeled or -unlabeled Escherichia coli and 20% total body surface area burn injury. Survival rate and the extent of translocation of E. coli were determined. MEASUREMENTS AND MAIN RESULTS: Feeding with diets supplemented with arginine, glutamine, and arginine plus glutamine and treatment with dehydroepiandrosterone reversed the susceptibility to infections caused by prednisone and burn injury. The beneficial effects were mediated by enhanced killing of translocated bacteria and/or by an improved gut barrier function. CONCLUSIONS: Dietary supplementation can reverse the susceptibility to infections caused by prednisone. Both arginine and glutamine as well as dehydroepiandrosterone may be useful therapeutic agents for preventing infections in steroid-treated patients.

Marcinkiewicz J, Grabowska A, Chain B. Nitric oxide up-regulates the release of inflammatory mediators by mouse macrophages. Eur J Immunol 1995 Apr;25(4):947-951.

Marz R. Medical Nutrition From Marz. Second Edition. Portland, OR. 1997.

Park KG. The Sir David Cuthbertson Medal Lecture 1992. The immunological and metabolic effects of L-arginine in human cancer. Proc Nutr Soc. 1993 Oct;52(3):387-401. (Review)

Yang CW, Kim YS, Kim J, Kim YO, Min SY, Choi EJ, Bang BK. Oral supplementation of L-arginine prevents chronic cyclosporine nephrotoxicity in rats. Exp Nephrol 1998 Jan;6(1):50-56.
Abstract: This study was performed to evaluate the effect of L-arginine (L-Arg) on the prevention of chronic cyclosporine (CsA) nephrotoxicity in rats. Rats pair-fed a low-salt diet (0.05%) were given CsA (15 mg/kg/day s.c.), CsA and L-Arg (L-Arg group, 1.25 g/l water), CsA and N-nitro-L-arginine methyl ester (L-NAME group, 70 mg/l water) or vehicle. After 28 days, the L-Arg group had a higher glomerular filtration rate compared to the CsA (0.42 +/- 0.05 vs. 0.31 +/- 0.06 ml/min/100 g, p < 0.05) and the L-NAME groups (vs. 0.19 +/- 0.04 ml/min/100 g, p < 0.05) and a significantly lower serum creatinine level compared to the CsA (0.70 +/- 0.06 vs. 0.92 +/- 0.12 mg/dl, p < 0.05) and the L-NAME groups (vs. 1.21 +/- 0.17 mg/dl, p < 0.05). The L-Arg group had less fibrosis, tubular injury (TI), and arteriolopathy than the CsA (fibrosis 0.39 +/- 0.14 vs. 0.74 +/- 0.15; TI 1.3 +/- 0.3 vs. 2.0 +/- 0.1; arteriolopathy 33 +/- 7 vs. 48 +/- 17, p < 0.05, respectively) and the L-NAME groups (fibrosis vs. 1.67 +/- 0.32, TI vs. 2.6 +/- 0.3, arteriolopathy vs. 63 +/- 10, p < 0.05, respectively). Plasma renin activity in the L-Arg group was less than in the CsA (18 +/- 2 vs. 23 +/- 3 ng Ang I/ml/h, p < 0.05) and the L-NAME groups (vs. 30 +/- 3 ng Ang I/ml/h, p < 0.05). Nitric oxide production in L-Arg group was higher than in the CsA (24.2 +/- 1.7 vs. 11.1 +/- 1.5 mumol/24 h, p < 0.05) and the L-NAME groups (vs. 8.4 +/- 1.0 mumol/24 h, p < 0.05). In conclusion, the nitric oxide pathway is associated with the pathogenesis of chronic CsA nephrotoxicity, and exogenous L-Arg supplementation is effective in reducing chronic CsA nephrotoxicity in rats.

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review)