BCAA is a group of three ketogenic essential amino acids (leucine, valine, isoleucine).
BCAA is called a branched chain because its structure has branches in the body of the molecule. BCAA is a free (non-protein) form and has a minimum amount in skeletal muscle, but the combination of these three essential amino acids constitutes approximately two-thirds of human skeletal muscle in protein form.
The BCAA is traded as crystalline powder or crystalline powder and is odorless but has a bitter taste. All BCAAs are readily soluble in formic acid but are sparingly soluble in water and almost insoluble in alcohol.
Since the enzyme BCAA aminotransferase does not exist in the liver where many other amino acids are converted, BCAA is metabolized only in muscle.
The rate-determining enzyme of BCAA metabolism is branched-chain keto dehydrogenase, which is in the muscle and is activated efficiently by exercise and fasting.
BCAA is used in various combinations and contents between leucine, valine and isoleucine.
Leucine oxidizes very easily and is most effective in stimulating insulin secretion from the pancreas.
Leucine lowers high blood sugar and stimulates growth hormone secretion.
In the pharmaceutical field, BCAA is used to maintain the nitrogen balance in patients after surgery for gastric cancer and to treat various liver injuries.
There are three targets for BCAA supplementation in liver disease: (1) hepatic encephalopathy, (2) liver regeneration, and (3) cirrhosis (Urata, 2007, Kawamura, 2009).
BCAA can improve hepatic encephalopathy by promoting detoxification of ammonia, correcting plasma amino acid imbalance, and suppressing the inflow of aromatic amino acids into the brain.
BCAA supplementation for hepatic encephalopathy is particularly effective for chronic liver injury with hyperammonemia and low blood BCAA levels.
BCAA’s effects on liver regeneration and nutritional status in the body are related to protein synthesis, hepatocyte growth factor secretion, glutamine production, and protein degradation (Holecek, 2010).
In recent clinical studies, it is possible to suppress muscle damage and muscle pain caused by exercise by oral loading with BCAA, suggesting improvement of muscle function over a long period of time. There is a controversy about whether there is an anabolic effect later.
However, research on the topic of anabolic effects is still incomplete because the methods for studying differences in muscle function and BCAA intake (the proportion of leucine, valine, and isoleucine) are not uniform.
There is no data showing the side effects of increasing the BCAA intake by healthy individuals with regard to the upper limit intake in the main foods of humans (4th ICAAS Workshop on Evaluation of Appropriate Amounts of Amino Acid Diet).
The only “model” exposed to extremely high amounts of BCAAs is maple syrup urine disease, a very rare genetic disease, or serious brain dysfunction, but useful models that overdose BCAAs in the general population (See Fernstrom, 2005 for an overview).
Patients with cirrhosis received high doses (approximately 12 grams of BCAA per day) for several months, but no side effects were reported (see Marchesini, 2005 for an overview).
According to a recent project supported by ICAAS (Elango, 2010), the average metabolic upper limit for oxidation of leucine in healthy subjects is 0.56 g / kg body weight, maintaining homeostasis of intake of leucine, one of the amino acids of BCAA. Control methods are established.
- Elango, R., Chapman, K., Rafii, M., Ball, R. O., Pencharz, P. B. (2010). Abstract for the Experimental Biology.
- Fernstrom, J. D. (2005). J. Nutrition, 135S, 1539 – 1546.
- Holecek, M. (2010). Nutrition, 26, 482-490.
- Jackman, S. R., Witard, O. C., Jeukendrup, A. E., Tipton, K. D. (2010). Med Sci Sports Exercice, 42, 962-970.
- Kawamura, E., Habu, D., Morikawa, H., Enomoto, M., Kawabe, J., Tamori, A., Sakaguchi, H., Saeki, S., Kawada, N., Shiomi. S. (2009). Liver Transpl., 15, 790-797.
- Marchesini, G., Marzocchi, R., Noia, M., Bianchi, G. (2005). J. Nutrition, 135S, 1596 – 1601.
- Shimomura, Y., Inaguma, A., Watanabe, S., Yamamoto, Y., Muramatsu, Y., Bajotto, G., Sato, J., Shimomura, N., Kobayashi, H., Mawatari, K. (2010). Int J Sport Nutr Exerc Metabolism, 20, 236-244.
- The 4th Workshop on the Assessment of Adequate Intake of Dietary Amino Acids (2005). J. Nutrition, 135S.
- Urata, Y., Okita, K., Korenaga, K., Uchida, K., Yamasaki, T., Sakaida, I. (2007). Hepatol Research, 37, 510-516.
Branched-chain amino acids in liver protection
A long-term high alcohol intake leads to severe liver damage and may directly cause liver cirrhosis. Unfortunately, what the word “high” means is not so clear yet. Patients with liver cirrhosis often have protein malnutrition and reduced physical activity. At the same time, they often report high blood levels of ammonia and imbalanced essential amino acids in blood. Practically all findings in cirrhotic patients have documented a dramatic decrease of branched-chain amino acids (BCAA) in plasma and imbalances in circulating levels of other essential amino acids. Considering the overall situation of a patient suffering with a liver damage or cirrhosis; nutritional support based on BCAA makes for a coherent nutritional story.
Indeed, long-term placebo controlled studies have been very supporting for the above concept, both in Japan and Europe. See: www.ncbi.nlm.nih.gov/pubmed/2606303 and www.ncbi.nlm.nih.gov/pubmed/12806613 The mechanism(s) for the beneficial effects of BCAA is probably mediated by their stimulating activity on hepatocyte growth factor, favoring liver regeneration. Some new studies (www.ncbi.nlm.nih.gov/pubmed/26058864 ) have also suggested that BCAA are essential in mediating efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of such channeling could be a significant contributor to mitochondrial dysfunction and liver damage. While major clinical test were conducted only in patients with advanced liver cirrhosis leading to successful development and use of BCAA-based medical foods for alcoholic liver cirrhosis in Japan; one wonders how nutritional supplementation with BCAA (perhaps combined with some nonessential amino acids) could serve to protect liver of otherwise healthy drinkers, especially those who have low protein intakes. In that target group, which is very large world-wide, medical science is less clear.
Unfortunately, such “scientific greyness” for pre-pathologic states is seen frequently in other illnesses since only sick people are sufficiently categorized and clinically researched. Therefore, much better knowledge is available on nutra-pharmaceutical drug treatments than on nutritional prevention. But, before we know more, make sure you have enough BCAA in your food before you go to that party…
Branched-chain amino acids (Bcaa) and delayed muscle soreness
Scientific debate continues on whether short-term dietary supplementation with branched-chain amino acids (BCAA, leucine, isoleucine, valine) can maintain a short-term net anabolic hormonal profile and decrease muscle cell damage during training, thereby enhancing recovery.
The key reasons for the controversy are simple and difficult at the same time; there are too many factors that influence exercise outcome and recovery. Among those, differential exercise models, differential intensity of exercise (unfortunately one has to exercise…), divergent doses of BCAA, single doses versus chronic intake, different ratios of BCAA, timing of ingestion (before, during or after exercise!), age, background nutrition and so on. Too many factors to count …
However, clinical testing with subjects (both genders) ingesting at least 5 grams of BCAA shortly prior to high-intensity resistance training are reasonably straightforward: BCAA substantially decrease muscle soreness, enhance recovery from exercise and consequently improve long-term performance. See:
BCAA (mainly leucine) are the literal keys to starting muscle synthesis, but there is very little non-protein BCAA in your muscles. Plus, their oxidation is triggered directly by physical exercise. The mechanism responsible for this phenomenon is attributed to activation of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, which catalyzes the key reaction of the BCAA catabolic pathway and is the rate-limiting enzyme in the pathway. So, if strenuous exercise starts the process of BCAA oxidation and you need BCAA to make new muscle, it is clear that BCAA have to be provided from other (read, dietary) sources.
Taken together, supplementation with sufficiently high doses of BCAA (at least 5 gram, out of which at least 2.5 gram should be leucine) immediately before intensive exercise has beneficial effects of decreasing exercise-induced muscle damage and promoting muscle-protein synthesis.
Among others: http://www.ncbi.nlm.nih.gov/pubmed/19997002 For those focused on overall nutritional balance … it does not really maters how much BCAA you are ingesting over long term in your proteins, what matters is the single drink of a high BCAA dose taken immediately prior to strenuous resistance training … the key messages were underlined!
Adverse effects of leucine overdose depend on dietary protein levels: identification of effective biomarkers by bio-transcriptomic analysis
This study was undertaken to identify reliable genetic biomarkers for the adverse effects of leucine (Leu) overdose in Sprague-Dawley rats by DNA microarrays.
It has long been known that the adverse effects of amino acid overdose depend on dietary protein levels.
Male rats were divided into 12 groups (n = 6) and fed a diet containing protein at low (6%), medium (12%) and high (40%) levels for 1 week.
Different levels of leucine were added to the diet (0, 2, 4, 8%).
Ingestion of 6% protein leucine content greater than 4% showed growth retardation and liver weight loss, but 12% or 40% protein with the same amount of leucine had no effect There wasn’t.
Six genetic marker candidates were identified through systematic data extraction.
Validating these biomarker candidates by ROC analysis using liver gene expression data obtained from another experiment using 0, 2, 3, 4, 8% leucine content in a low protein diet The sex was examined.
The biomarker candidate area under the concentration curve (AUC) values all exceeded 0.700, suggesting the effectiveness of the marker candidate as an indicator of leucine overdose.
The cut-off value according to the ROC curve of the genetic marker panel obtained by the multiple regression analysis of the genetic marker indicates that adverse effects occur when the leucine content exceeds 3%.
In conclusion, the genetic marker panel suggests that dietary supplementation with a leucine content of 2% for male rats is a non-toxic dose (NOAEL) at low protein (6%).
Correlation between branched-chain amino acid levels and insulin resistance improvement during weight loss
Insulin resistance (IR) improves with weight loss, but the response is not constant.
In this experiment, we hypothesized that metabolomic profiling identifies biomarkers that predict changes in IR due to weight loss.
Profiling based on mass spectral analysis of 60 target metabolites and biochemical analysis of NEFA (non-esterified fatty acid), β-hydroxybutyrate, ketone, insulin, glucose in WLM trial Baseline and 6-month plasma samples from 500 participants who lost more than 4 kg during the Phase 1 period.
It is based on a homeostasis model assessment of insulin resistance (HOMA-IR) and changes in HOMA-IR with some weight loss (∆HOMA-IR).
A mixed model adjusted for principal component analysis (PCA) and race, gender, baseline weight, and weight loss was used.
The results were confirmed in an independent cohort of test animals (n = 22). The average weight loss was 8.67 ± 4.28 kg, the average ∆HOMA-IR was -0.80 ± 1.73, and the range was -28.9 to 4.82).
Baseline PCA-derived factor 3 (branched chain amino acids [BCAA] and related catabolic metabolites) is correlated with baseline HOMA-IR (r = 0.50, p <0.0001) and ∆HOMA-IR (P <0.0001). ∆HOMA-IR increased linearly with increasing third quartile of baseline factor. There was little correlation between weight loss and ∆HOMA-IR (r = 0.24). These findings were validated in an independent cohort using factors consisting of BCAA and related metabolites that predict ∆HOMA-IR (p = 0.007). A cluster of metabolites consisting of BCAAs and related analytes predicts HOMA-IR improvement independent of weight loss. These results may help identify individuals who are most likely to benefit from moderate weight loss and elucidate new mechanisms of IR in obesity.
Inhibition of hepatoma cell insulin-induced proliferation of branched-chain amino acids by inducing apoptosis through mTORC1- and mTORC2-dependent mechanisms
Branched-chain amino acid (BCAA) supplementation has been reported to reduce the incidence of liver cancer in obese patients with cirrhosis or obese and diabetic model animals that developed cancer.
Whether BCAA directly suppresses the growth of liver tumor cells under hyperinsulinemia conditions remains unclear.
The goal of this study is to determine the effect of BCAAs on insulin-induced proliferation of liver tumor cells and the underlying mechanism.
BCAA suppressed insulin-induced proliferation of H4IIE cells and HepG2 cells.
H4IIE cells did not affect cell cycle progression, but suppressed apoptosis by suppressing anti-apoptotic gene expression and inducing proapoptotic genes by inactivating PI3K / Akt and NF-κB signaling pathways Increased.
Furthermore, it not only promotes a negative feedback loop from the mammalian target of rapamycin complex 1 (mTORC1) / S6K1 to the PI3K / Akt pathway, but also inhibits the activity of mTORC2 kinase on Akt, thereby inhibiting the PI3K / Akt pathway Proved to be. The results of this study suggest that BCAA supplementation can suppress the progression of liver cancer by suppressing insulin-induced PI3K / Akt and further suppressing the anti-apoptotic pathway, and BCAA is an obese patient with progressive liver disease This indicates the possibility of being effective.
Dose-dependent effect of leucine supplementation on muscle mass maintenance in cancer cachexia mice
Cancer cachexia is characterized by muscle wasting and is associated with increased morbidity and mortality.
Because leucine supplementation may increase muscle protein synthesis and reduce protein degradation, leucine dietary supplementation can be used for muscle weight and muscle protein degradation markers (atrogin) in a cachexic mouse model of C26 tumors. And murf mRNA).
Male CD2F1 mice were inoculated subcutaneously with tumor cells (tumor mice; TB) or sham (control group; C).
Mice received a standard diet or a diet supplemented with leucine [1gr (TB1Leu) / kg or 8gr (TB8Leu) / kg].
TB and C were administered leucine 8.7% / g protein, TB1Leu was administered leucine 9.6% / g protein, TB8Leu was administered leucine 14.6 / g protein, and 21 days later, body weight, plasma amino acid concentration, tumor size And gastrocnemius muscle mass (mG), anterior tibial muscle (mTA), long calf extensor (mEDL) and soleus muscle (mS).
In tumor-bearing (TB) mice, carcass and skeletal muscle were reduced and atrogin and murf mRNA levels in mEDL were increased.
Leucine supplementation reduced muscle loss in a dose-dependent manner: TB8Leu had + 23% mG muscle mass and + 22% mTA compared to TB (p <0.05). However, leucine supplementation did not change the mRNA levels of atrogin and murf. In TB, total plasma amino acid concentrations increased, particularly taurine, lysine, arginine and alanine concentrations (p <0.05). Supplementation with leucine suppressed the increase in total plasma amino acid concentration (p <0.05). Regardless of changes in muscle proteolytic markers, supplementation with leucine reduced changes in muscle wasting and plasma amino acid concentrations in tumor-caused mice.
ヒトの栄養分としては、リジンは穀物を主食とする場合の第1制限アミノ酸として認識されており、発展途上地域の貧困層に不足しています(Scrimshaw, 1973)。リジンが不足気味の食生活を送っている民族的、文化的に多様な層において、リジンの強化によるタンパク質の品質の著しい改善やその後の子どもの成長の促進について記録されています（Pellet & Ghosh,2004; Hussain,2004;Zhao,2004）。最近の研究によれば、急性感染症の疾病状況でリジンやその他の必須アミノ酸の必要性が高まることが示唆されています（Kurpad,2003,Smriga,2004）。アフリカ西部の人々に対する最新の研究によれば、食事におけるリジンの補給により、子どもの下痢やヒトの呼吸器疾患の罹患率を軽減させることができました（Ghosh,2010）。あるICAAS会員企業では、上記の臨床データ（図）をふまえ、アフリカ西部における研究と開発を積極的に進めています。
- Ghosh, S., Smriga, S., Vuvor, S., Suri, D., Mohammed, H., Armah, S., Scrimshaw, N. S. (2010). Am J Clin Nutrition, 92, 928-939.
- Griffith, R. S., Walsh, D. E., Myrmel, K. H., Thompson, R.W., Behforooz, A. (1987). Dermatologica,175, 183-190.
- Hussain, T., Abbas, S., Khan, M. A., Scrimshaw, N. S. (2004). Food and Nutrition Bulletin, 25(2):114-22.
- Kurpad, A. V., Regan, M. M., Raj, T., Vasudevan, J., Kuriyan, R., Gnanou, J. (2003). Am J Clin Nutrition, 77, 101-108.
- Pellett, P.L., Ghosh, S. (2004). Food and Nutrition Bulletin, 25, 7.
- Scrimshaw, N. S., Taylor, Y., Young, V. R. (1973). Am J Clin Nutrition, 26, 965-972.
- Smriga, M., Ghosh, S., Mouneimne, Y., Pellett, P. L., Scrimshaw, N. S. (2004). Proceedings of the National Academy of Sciences of the United States of America, 101, 8285-8288.
- The 6th Workshop on the Assessment of Adequate Intake of Dietary Amino Acids (2007). J. Nutrition, 137, Supplement.
- Zhao, W., Zhai, F., Zhang, D., An, Y., Liu, Y., He, Y., Scrimshaw, N. (2004). Food and Nutrition Bulletin, 25, 123-129.
Lysine and herpes recurrence
L-lysine (lysine), is an essential amino acid which means our body is unable to produce it. One has to ingest lysine from foods or dietary supplements. Besides regular protein synthesis, lysine is important for proper growth, and it plays an essential role in the production of carnitine, a nutrient responsible for transferring fatty acids into energy and consequently helping lower circulating cholesterol.
Some studies suggested that taking lysine on a regular basis may help prevent outbreaks of cold sores and herpes simplex. Herpes simplex is a common viral infection of the skin or mucous membranes. The lesions caused by this infection are often painful, burning and tend to recur in most patients. Experts generally agree that lysine supplementation may not prevent herpes, but may reduce recurrences or severity of recurring outbreaks. Several well-controlled clinical studies reported that lysine was an effective agent for reduction of occurrence and also healing time of recurrent herpes infections (i.e., www.ncbi.nlm.nih.gov/pubmed/3115841 ). In the last specific report, three grams of lysine taken during 6-month-long test period were significantly effective in reducing both occurrence and severity. A comparable outcome was reported in a longer (12 months) double-blind cross-over study with as little as one gram lysine per day (www.ncbi.nlm.nih.gov/pubmed/6438572 ), but not with lower doses (< 0.62 g per day) (http://www.ncbi.nlm.nih.gov/pubmed/6435961 ). Initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases (enzymes), one of them being lysine-specific demethylase 1. Basically, inhibition of one of those enzymes results in blocking infection and reactivation of the disease. The mechanism of lysine action is not clear yet, but it may involve the above pathway and/or antagonism of arginine pathways. Finally, assuming that daily supplemental dose of 3 grams of lysine per day is effective in herpes simplex; it is important to note that at that dose (and at much higher ones), lysine is a safe amino acid (www.ncbi.nlm.nih.gov/pubmed/9013429 ). Besides its prophylactic effect in herpes, it helps the body in absorbing calcium, and it plays a role in the formation of collagen, which would suggest that some caution would be warranted in the cases of co-administration of very high doses of calcium and lysine.
Lysine as the 1st Limiting amino acid in cereals
Many people around the world consume cereal-based diets, either for economic, religious or ethical reasons. In most cases such diets, supplemented with vegetables and legumes, are sufficient to provide essential amino acids needed by our bodies for grow and/or sustenance. In some cases, though, one or several essential amino acids can be severally limited. Most notable case is lysine, which is by far the most limiting amino acid in cereal diets.
Fortification with lysine to improve the protein value of diets have been supported well through several intervention trials conducted in developing regions. Among others, see:
While the WHO/FAO recommendations call for at least 39 mg of lysine per person per day, some poor populations eat diets that do not reach such levels. It is therefore not a major surprise that even short (3-month-long) fortifications with lysine triggered some substantial improvements in growth of children, immune parameters and overall nutritional status of the tested populations. Adding lysine alone diminished the overall protein deficiency by as much as 50% – making it an effective and very affordable way to tackle protein intake issues.
Of course, the improvement of dietary quality must be the long-term aim with several approaches. Over the last several decades, increases have occurred in the availability of food energy and total protein even in developing countries. However, for the very poorest developing countries over the same period, changes have been almost nonexistent, and the values for some nutritional indicators have even declined due to political unrest. This adds to the significance of reaching out to affected populations, especially growing children, with immediate and effective solutions in a form of fortifications.
In the case of lysine, the issue is further strengthened by the indications that the lysine benefits go far beyond purely nutritional support. Data obtained from Syria, Bangladesh and Ghana http://www.ncbi.nlm.nih.gov/pubmed/15159538 and http://www.ncbi.nlm.nih.gov/pubmed/20720257 indicated that dietary lysine provided benefits that were no fully linked to nutrition. It reduced morbidity caused by diarrhea and improved mental health of the tested subjects. Considering that poor populations ingest diets poor in lysine from very early age, the results are shocking and call for immediate enforcement of dietary policies.
Finally, no relevant tests have been conducted in rich countries among vegetarians or elderly who avoid meat products. But, the message is clear; essential amino acid content of your diet, and especially a diet of your small kids, is very important!
Effects of L-lysine supplementation on the health and morbidity of patients in poor households around Accra (Ghana)
L-Lysine affects diarrhea and anxiety via effects on serotonin receptors, enhanced intestinal repair, and sodium chloride-dependent opioid peptide transport. The objective of this study was to investigate the effects of lysine supplementation on morbidity, growth, and anxiety in children and adults of peri-urban areas of Accra, Ghana. In a double-blind randomized trial, the effect of lysine supplementation (1 g lysine/d) compared with that of placebo was examined in 2 groups of men, women, and children (n = 271). Primary outcomes included diarrheal and respiratory morbidity, growth, and anxiety and complement C3, C-reactive protein, serum cortisol, transferrin, and ferritin values. Independent-sample t tests, odds ratios, generalized estimating equations, 4-parameter sinusoid regression, and generalized linear models were used.
Thirty percent of men, 50% of women, and 15% of children were at risk of lysine inadequacy. Supplementation in children reduced diarrheal episodes [19 lysine, 35 placebo; odds ratio (OR): 0.52; 95% CI: 0.29, 0.92; P = 0.046] and the total number of days ill (21 lysine, 47 placebo; OR: 0.44; 95% CI: 0.26, 0.74; P = 0.034). Mean days ill per child per week (0.058 ± 0.039 lysine, 0.132 ± 0.063 placebo; P = 0.017) were negatively associated with weight gain with control for baseline weight and study group (P = 0.04). Men had fewer coryza episodes (23 lysine, 39 placebo; OR: 0.60; 95% CI: 0.36, 1.01; P = 0.05), total number of days ill (lysine: 130; placebo: 266; OR: 0.51; 95% CI: 0.28, 0.93; P = 0.03), and mean days ill per person per week (lysine: 0.21 ± 0.23; placebo: 0.41 ± 0.35; P = 0.04). Serum ferritin (P = 0.045) and C-reactive protein (P = 0.018) decreased in lysine-supplemented women but increased in placebo-supplemented women. Lysine supplementation reduced diarrheal morbidity in children and respiratory morbidity in men in Ghana.
トリプトファン（Trp）は9つの必須アミノ酸の1つで、毎日の食生活の中で摂取しなければなりません。成人男性のトリプトファンの所要量は4.0mg/kg（体重）です。1970年代以降、トリプトファンが神経終末による神経伝達物質セロトニンの形成速度に影響し、またメラトニンの前駆物質でもあることが発見されたため、トリプトファンを摂取して精神的ストレスを軽減したり、睡眠を改善するアイディアが取り入れられています。脳内トリプトファンはトリプトファン及び炭水化物の血漿内供給に共依存しています（Fernstrom, 1983 & 1991）。反対に他の大型の中性アミノ酸（LNAA：チロシン、フェニルアラニン、ロイシン、イソロイシン、バリン）の血中循環濃度の影響を受けており、トリプトファンの生成は栄養的側面に依存しています。食事によるトリプトファンの供給が不足すると、急速かつ深刻な脳内セロトニンの活性低下をもたらします。トリプトファンが不足すると、季節性情動障害、不安症、炭水化物渇望、月経前症候群および日々のストレスへの対処能力を悪化させます（Blokland et al.,2002）。
トリプトファン欠乏モデルのヒトへの応用では、トリプトファン欠乏の否定的な結果がセロトニン欠乏により生じているだけでなく、主としてモノアミン作動系間の複雑な相互作用により生じていることが示唆されています(Reilly et al., 1997; Van der Does, 2001; Delgado, 2000)。しかし、トリプトファンの補助食品への使用に関しては依然として見解の一致をみていません。比較臨床試験では、トリプトファン栄養補助食品を単独あるいは炭水化物と組み合わせて摂取すると、ストレスの状態を緩和し（Maes et al., 1999)、比較的軽度の認知力低下を軽減することが示されています（Markus et al.,2002）。
さらに、トリプトファンにはビタミンB3の生産に不可欠であり、また、変換酵素の生産にはビタミンB6、亜鉛、ビタミンCが必要です。比較臨床試験では、トリプトファンまたは5-ヒドロキシトリプタミン（トリプトファンを分解する際にセロトニンへの変換過程で生じる半生成物）が子供の過活動児童症を抑制するのに役立つことが示唆されています（Rucklidge et al.,2009）。
- Blokland, A., Lieben, C. & Deutz, N. E. (2002). Anxiogenic and depressive-like effects, but no cognitive deficits, after repeated moderate tryptophan depletion in the rat. Journal of Psychopharmacology, 16, 39-49.
- Delgado, P. L. (2000) Depression: the case for a monoamine deficiency. Journal of Clinical Psychiatry, 61, 7-11.
- Fernstrom, J. D. (1991). Effects of the diet and other metabolic phenomena on brain tryptophan uptake and serotonin synthesis. Advances in Experimental Medicine and Biology, 294, 369-76.
- Fernstrom, J. D. (1983). Role of precursos availability in control of monoamine biosynthesis in brain. Physiological Reviews, 63, 484-486.
- Maes, M., Lin, A. H., Verkerk, R., Delmeire, L., Van Gastel, A., Van der Planken, M. & Scharpe, S. (1999). Serotonergic and noradrenergic markers of post-traumatic stress disorder with and without major depression. Neuropsychopharmacology, 20, 188-97.
- Markus, C. R., Olivier, B. & de Haan, E. H. F. (2002). Whey protein rich in lactalbumine increases the ration of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects. American Journal of Clinical Nutrition, 75, 1051-1056
- Reilly, J. G., MCTavish, S. F. & Young, A. H. (1997). Rapid depletion of plasma tryptophan: a review of studies and experimental methodology. Journal of Psychopharmacology, 11, 381-392.
- Rucklidge, J. J., Johnstone, J., Kaplan, B. J. (2009). Nutrient supplementation approaches in the treatment of ADHD. Expert. Rev. Neurother. 9, 461-76.
- Van der Does, A. J. (2001). The effect of tryptophan depletion on mood and psychiatric symptoms. Journal of Affective Disorders, 64, 107-119.
Tryptophan as a help in depression
Alteration of tryptophan metabolism elicited by inflammation has been recently gaining some medical attention as a novel concept to explain the pathophysiology of depression. The kynurenine pathway is one of the tryptophan metabolic pathways, and it is an alternative pathway to tryptophan being metabolized into the “calming” neurotransmitter serotonin. Pro-inflammatory cytokines strengthen the kynurenin pathway, deprive the serotoninergic neurons of tryptophan source and thus reduce serotonin synthesis. The resultant decrease in serotonin production in the specific regions of the brain relates to the prevailing monoamine hypothesis of depression.
In addition, the above changes could decently explain the hippocampal atrophy that appears in chronic depression and which is probably also associated with decreases of serotonin. Because pro-inflammatory cytokines also activate the endocrine (HPA) axis, these imbalances may inhibit the hippocampal negative feedback system. In that way, changes in the tryptophan metabolism or decreases in dietary intake of tryptophan itself, may also relate to the HPA axis-hyperactivity hypothesis of major depression https://www.ncbi.nlm.nih.gov/pubmed/20153778 Taken all together, inflammation shifting tryptophan away from the serotonin production in the brain may contribute to depression in a powerful double pathway. Watch your dietary tryptophan …
Essential amino acid tryptophan had been one of the most popular topics of nutritional neuroscience studies of the 1980s. The scientific (and commercial) interest was directly linked to the ability of tryptophan to cross the blood-brain barrier, which separates the brain from the rest of the body, and to stimulate synthesis of an inhibitory brain neurotransmitter serotonin that is involved in etiology of sleep, stress and mood regulation. Indeed, even a short-term deficiency of dietary tryptophan substantially worsened mental health and sleep quality in both healthy and depressed people because it affected serotonin availability (www.ncbi.nlm.nih.gov/pubmed/19721848, www.ncbi.nlm.nih.gov/pubmed/15935252). On the other hand, tryptophan supplementation (at certain doses) increased subjective drowsiness, leading to better onset of sleep and decreased pain sensitivity, sometime more efficiently than analgesic drugs did. www.ncbi.nlm.nih.gov/pubmed/6473667 Importantly, unlike many hypnotics, tryptophan did not impair sensorimotor performance.
Clinical research was suddenly terminated in 1990; shortly after it was reported that a single batch of a dietary supplement containing tryptophan caused a deadly disease. Soon afterwards, it was documented that the direct cause of the disease was an impurity present in the problematic supplement. Products that contained tryptophan with sufficiently tight specifications (typically US Pharmacopeia and recently also Food Chemical Codex (FCC)) had not been linked to any problems. Consequently, tryptophan was re-approved in major markets in middle 2000s; and the scientific interest in its application has been rising again.
Scientific experiments conducted since 2005 only re-confirmed that tryptophan can improve sleep quality and mood. Elderly and middle-age groups have been especially targeted in clinical studies (www.ncbi.nlm.nih.gov/pubmed/22622709, www.ncbi.nlm.nih.gov/pubmed/25693900). When the tryptophan-containing supplements were taken 60-90 min before bedtime in middle-aged women (www.ncbi.nlm.nih.gov/pubmed/25572038), a feeling of happiness before going to bed was consistently found. Authors of the last study reported that daily consumption of a low-dose tryptophan supplement was beneficial even on cognitive functions. Taken together, clinical research of the last decade has showed again that tryptophan loading is effective for improving mood in vulnerable subjects, and improving sleep in middle-aged and elderly adults with some minor sleep disturbances.
Are there side effects from high-quality modern tryptophan supplementation? Though the literature is thin, occasional side effects, seen mainly at higher doses (70-200 mg/kg body weight), include tremor, nausea, and dizziness, and may occur when tryptophan is taken with a drug that enhances serotonin function (e.g., antidepressants). A recent toxicological study conducted in healthy females documented that tryptophan alone is safe up to 5 grams per day (www.ncbi.nlm.nih.gov/pubmed/23616514 ). The last report and absence of side-effect in controlled studies document that controlling quality is much more important than controlling maximum daily dose – an observation constantly reported for all essential and semi-essential amino acids.
時間栄養学 （Chrononutrition） は時間生物学の一分野で、健康に良く、生体リズムや身体能力の改善に有効な時間に食事を摂取するのがよいという考え方が確立されている。
Essential amino acid histidine and colitis
An increased level of blood lipids is one of the risk factors for cardiovascular disease. Current medical classification schemes and treatment levels for hyperlipidemia emphasize the pharmaceutical use of statins as the preferred class of drugs to lower elevated low density lipoprotein cholesterol. There are other drug classes to augment or perhaps substitute for statins, such as fibrates and niacin. Indeed, research has raised the question whether or not the current guidelines are sufficiently inclusive and effective. New guidelines are expected to be released in the near future, but in the meantime, physicians are facing insecurity when advising patients on how to lower dangerous low density lipoprotein cholesterol.
In that respect, it is worthwhile to notice that simple dietary supplementation with essential amino acids (EAA) could lower plasma triglyceride and improve glucose metabolism in humans. In a clinical study conducted with elderly a few years back, circulating TG concentrations were reduced ~20% from the starting value, while total caloric intake was not significantly affected by the EAA supplements ingested daily over 16 weeks. (www.ncbi.nlm.nih.gov/pubmed/19041223 ). The most recent clinical study was conducted in subjects who were 50 years or older and had a documented plasma plasma triglycerides elevated at >150 mg/dL. The outcome of the study further showed that a dietary supplementation of leucine-enriched EAA, in a combination with phytosterols, promoted favorable reductions of blood lipids in individuals with hyperlipidemia (www.ncbi.nlm.nih.gov/pubmed/26726312 ).
Since elevating dietary intake of EAA is relatively simple and affordable, one could only hope that such an intervention would be incorporated into new medical classification schemes and treatment levels for hyperlipidemia. This is especially true when considering that lysine-enriched EAA, perhaps in combination with arginine, also substantially increase lean body mass, improve strength as well as physical function compared to baseline values in elderly individuals. (see, www.ncbi.nlm.nih.gov/pubmed/18294740)
L-フェニルアラニンは、タンパク質を構成する必須アミノ酸の一種で、芳香族アミノ酸に分類される。L-フェニルアラニンは、肝臓でL-チロシンに代謝され、カテコールアミン（ノルアドレナリンやドーパミンなど）の前駆体として知られている。必須アミノ酸は、食事から摂取しなければならない栄養成分で、肉類、魚介類、卵、および、乳製品などの様々な食品中に、タンパク質を構成する成分または遊離型アミノ酸として存在する。日本人のL-フェニルアラニンの平均摂取量は、男性3.51g/日、女性2.97g/日と報告されている（Kato et al., Jap. Soc. Nutri. Diet. 71 (2013)）。近年、生理活性を目的としたサプリメントなどに用いられており、脳機能 （Birkmayer et al., J Neural Transm. 59 (1984)), 鎮痛 (Walsh et al., Arch Phys Med Rehabil. 67 (2013)）, 皮膚 (Antoniou et al., Int J Dermatol. 28 (2014))などへの影響が報告されている。
L-フェニルアラニンの安全性に関する以下の報告がある。非臨床安全性試験では、ラットにL-フェニルアラニンを 0.5、1.5、および、5.0 %混餌の条件で4週間の毒性試験が実施された。本試験の結果から、L-フェニルアラニンの無毒性量は、雄で1.5 %混餌 （1,548 mg/kg/日）、雌で0.5 %混餌 (1,555 mg/kg/日）と報告(Shibui et al., Fund Toxicol Sci 1 (2014)) されている。ヒトでの安全性に関わる試験では、健康な成人男性６名にL-フェニルアラニンを3 g/日の投与量での単回投与試験が実施された。本試験の結果から、L-フェニルアラニンの3 g/日の単回投与では、有害事象は観察されないことが報告（Ueda K et al., J. the Int. Soc. Sports Nutri.14 (2017)）されている。
Glycine and sleep
A substantial number of our posts so far have been focusing on the essential or semi-essential amino acids which are not sufficiently synthetized within mammalian bodies. Dietary supplementation with those amino acids in specific situations makes intuitive sense. But, the word “non-essential” is misleading and in many cases they can provide “very essential” support to our organism. Let’s look even at the simples non-essential amino acid – glycine. Glycine has only tiny hydrogen on its side-chain and thus it is the smallest of the twenty amino acids that build natural proteins. A typical diet contains about 2 grams of glycine daily. The primary sources are protein-rich foods including meat, fish and legumes. Glycine is used as a part of nutritional treatments in diseases such as schizophrenia or benign prostatic hyperplasia (BPH). It is also used to protect kidneys from the harmful side effects of certain drugs used after organ transplantation. What about regular healthy population? Recent clinical studies have shown that glycine dietary supplementation (3 gram) can help to improve sleep quality and mental performance on the following morning – especially in slightly sleep-deprived people www.ncbi.nlm.nih.gov/pubmed/22529837.
Interestingly, while improving sleep and shortening time between going to bed and falling asleep, glycine did not significantly affect either plasma melatonin concentration before or during the night, or the expression of “circadian clock genes” such as Bmal1 and Per2. However, glycine induced an increase in the neuropeptides arginine vasopressin and vasoactive intestinal polypeptide in the light period and probably promoted sleep also via peripheral vasodilatation through the activation of NMDA receptors in the suprachiasmatic nucleus (a part of the central nervous system). www.ncbi.nlm.nih.gov/pubmed/25533534. Moreover, glycine reduced slightly core body temperature before and during sleep, which is also a very important aspect of sleep regulation since the start of sleep is known to involve a decrease in the core body temperature www.ncbi.nlm.nih.gov/pubmed/22293292.
In terms of safety, nine grams of glycine (single ingestion) were demonstrated to be safe in adult humans (Inagawa et al., “Seikatsu Eisei” 2006, 50(1), 27-32), which is to be expected considering innate production and intake of glycine from foods. Taken together, the smallest amino acid makes a potentially big contribution to improving our quality of life and it does not look so “small” anymore in my eyes! Indeed, successful glycine supplements that are based on the above clinical science, are already being marketed in Japan to improve sleep.
また、アルギニンには多くの効能があります。アルギニンの摂取により、血管拡張1)、血流改善1,2)、また成長ホルモンの分泌を促すことはよく知られています3)。アルギニンは細胞傷害性を増強し、ナチュラルキラー細胞（NK細胞;抗体独立性のリンパ細胞）やリンホカイン活性化キラー細胞（LAK細胞；リンホカインによって誘導される活発な細胞傷害性を有するリンパ細胞）の免疫反応を促進します4）。アルギニンはインスリンの分泌を促すことが知られており、インシュリン分泌値を測定するのに非グルコース性分泌促進剤（分泌を起こすか、または分泌を刺激する薬剤) として使用されます5)。アルギニンは肝臓内の尿素（オルニチン）回路の構成要素としてアンモニアの解毒に関与しており6)、解毒促進効果を示します7）。アルギニンはアルギナーゼの作用により、オルニチン、ポリアミン前駆体に変換されます8,9)。ポリアミンは、組織増殖に関与することが証明されています9)。アルギニンは経口摂取で吸収されることが知られており10）、また多アルギニンの経口摂取は動物及びヒトにおいて効果があることが多くの事例で示されています3,11,12)。ヒトの食物でのアルギニンの上限摂取量に関して、副作用を示す記録はほとんどありません （第６回 アミノ酸の食事による適量摂取の評価に関するICAASワークショップ）13）。成人被験者においてアルギニンの筋肉増強や血流の改善効果を検証した臨床試験によると、改善に必要な一日摂取量は1－8gです。1,2,14)。アルギニン摂取に起因する望ましくない副作用は報告されていません。最近提唱されているOSL（Observed Safe level：安全性が確認されている一日摂取量）では、アルギニンのOSLは20g/日です15)。ラットを用いたアルギニンの急性経口毒性試験では、半数致死量（LD50）は16g/kg（体重）です16)。
- Hambrecht R. Hilbrich L. Erbs S. Gielen S. Fiehn E. Schoene N. Schuler G. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation.Journal of the American College of Cardiology.35(3):706-13, 2000
- Wolf A. Zalpour C. Theilmeier G. Wang BY.Ma A. Anderson B. Tsao PS.Cooke JP.Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans.Journal of the American College of Cardiology.29(3):479-85, 1997
- Besset A. Bonardet A. Rondouin G. Descomps B. Passouant P. Increase in sleep related GH and Prl secretion after chronic arginine aspartate administration in man.Acta Endocrinologica.99(1):18-23, 1982
- Brittenden J. Park KG.Heys SD.Ross C. Ashby J. Ah-See A. Eremin O. L-Arginine stimulates host defenses in patients with breast cancer.Surgery.115(2):205-12, 1994
- Eremin O. ed. L-Arginine:Biological aspects and clinical application.Chapman & Hall.15-8, 1997
- Rodwell VW.Chapter 31:Catabolism of Proteins and of Amino Acid Nitrogen. in Harper’s Biochemistry 25th Edition.Murray RK.Mayes PA.Rodwell VW.Granner DK eds.McGraw-Hill/Appleton & Lange.NY.USA.313-22, 1999
- Bessman SP.Shear S. Fitzgerald J. Effect of arginine and glutamate on the removal of ammonia from the blood in normal and cirrhotic patients.New England Journal of Medicine.256(20):941-3, 1957
- Rodwell VW.Chapter 32:Catabolism of the Carbon Skeletons of Amino Acids. in Harper’s Biochemistry 25th Edition.Murray RK.Mayes PA.Rodwell VW.Granner DK eds.McGraw-Hill/Appleton & Lange.NY.USA.323-46, 1999
- Rodwell VW.Chapter 33:Conversion of amino acids to specialized products. in Harper’s Biochemistry 25th Edition.Murray RK.Mayes PA.Rodwell VW.Granner DK eds.McGraw-Hill/Appleton & Lange.NY.USA.347-58, 1999
- Tangphao O. Grossmann M. Chalon S. Hoffman BB.Blaschke TF.Pharmacokinetics of intravenous and oral L-arginine in normal volunteers.British Journal of Clinical Pharmacology.47(3):261-6, 1999
- Elam RP.Morphological changes in adult males from resistance exercise and amino acid supplementation.Journal of Sports Medicine & Physical Fitness.28(1):35-9, 1988
- Barbul A. Rettura G. Levenson SM.Seifter E. Wound healing and thymotropic effects of arginine: a pituitary mechanism of action.American Journal of Clinical Nutrition.37(5):786-94, 1983
- The 6th Workshop on the Assessment of Adequate Intake of Dietary Amino Acids.The Journal of Nutrition.137, Supplement, 2007.
- Elam RP.Hardin DH.Sutton RA.Hagen L. Effects of arginine and ornithine on strength, lean body mass and urinary hydroxyproline in adult males.Journal of Sports Medicine & Physical Fitness.29(1):52-6, 1989
- Shao A. Hathcock JN.Risk assessment for the amino acids taurine, L-glutamine and L-arginine.Regulatory Toxicollogy & Pharmacology.50(3):376-99, 2008
- Amino Acid Data Book.Japanese Society for Amino Acid Sciences.2010
Is there anything L-arginine cannot do?
The semi-essential amino acid L-arginine has been used for years as an important part of medical foods; mainly due to its effect on ammonia clearing. It has been also included in intravenous nutrition of pre-term infants since they cannot synthetize it sufficiently. In adult people, L-arginine contributes to vasodilation and as a key stimulant of nitric oxide release affects plethora of physiological functions.
Beyond the general medical care and nutrition, L-arginine is used in tooth pastes intended for tooth sensitivity, because it helps decreasing the formation of dental plaque. Very recently, a research group at University of Michigan (USA) reported that L-arginine also breaks down existing dental plaque, which could further aid in avoiding cavities and oral diseases (www.ncbi.nlm.nih.gov/pubmed/25946040 ). The authors hypothesized that L-arginine is able to change how plague cells stick together, by lowering adhesive capacity of bacterial parts of dental plague to stick to tooth surface. Current approaches to dental plaque control are typically based on antimicrobial agents that directly kill plague bacteria, however the side effects of those chemicals has been open to critique for years, due to overuse and unknown long-term toxicity. In that respect, the naturally-occurring amino acid L-arginine may offer a substantially safer approach to the key problems of dental hygiene.
Arginine and Erectile Dysfunction
Erectile dysfunction is often considered as one of early signs of vascular disease (see last week’s post) due to its high prevalence in patients with cardiovascular problems. Indeed, evidence indicates that deficiency in endothelial factors contribute to micturition disorders, especially in erectile dysfunction. By far, the most important endothelial factor is nitric oxide, which is formed from arginine with the help of nitric oxide synthase. Two possible causes of such a deficiency are plasma and tissue lack of key substrates (mainly arginine) combined with increased levels of endogenous inhibitors of nitric oxide synthase (ADMA) (i.e., Sánchez A1, Contreras C, Martínez MP et al. PLoS One. 2012;7(4):e36027 ).
Consequently, the semi-essential amino acid arginine has been studied as a nutritional treatment in mild erectile dysfunction – both in laboratory animals and humans. In the newest double-blind, placebo-controlled, two-way crossover randomized clinical trial (the most sophisticated testing method applied to humans); twenty-six patients with mild erectile dysfunction received eight grams of arginine with or without conventional medicines. The results showed that the oral administration of arginine (with aspartate-adenosine monophosphate) was effective, very well tolerated and could be used as a safe first-line therapy (Neuzillet Y, Hupertan V, Cour F et al. Andrology 2013;1(2):223-228). Similarly, the positive role of arginine was demonstrated in sixty-one patients who had blood ratio of arginine to ADMA, which is an inhibitor of nitric oxide synthase, substantially lower when compared to controls. This study indicated that elevation of arginine causally contributed to the disease treatment (Paroni R, Barassi A, Ciociola F et al. Int J Androl. 2012;35(5):660-667).
Another study conducted with fifty-four erectile dysfunction patients in Italy found that three months of arginine treatment led to a small, but statistically significant improvement in total and single parameters of the disease. The authors concluded that, “the favourable cardiovascular effects of nutraceuticals might also reflect on male sexual function with possible implication in the treatment and prevention of erectile dysfunction” (Gianfrilli D, Lauretta R, Di Dato C et al. Andrologia. 2012;44 Suppl 1:600-604). Similar results were obtained with Japanese patients (Aoki H, Nagao J, Ueda T et al. Phytother Res. 2012;26(2):204-207).
Most importantly, ISSM Standards Committee for Sexual Medicine (Porst H, Burnett A, Brock G et al. J Sex Med. 2013;10(1):130-171) recently made a rigorous and newly updated overview on currently used and available conservative treatment options for erectile dysfunction with a special focus on their efficacy and tolerability. Oral administration of arginine (3-5 g) alone was recognized as a level 2 treatment, and orally applied arginine in a combination with appropriate medicines as the highest (level 5) treatment for the disease.
Arginine and the Cardiovascular System
The amino acid arginine is the substrate of endothelial nitric oxide synthase and the main precursor of nitric oxide (NO) in the vascular endothelium. Compromised production of NO may cause serious problems in endothelial equilibrium; therefore, numerous therapies have been investigated to assess the possibility of reversing endothelial dysfunction by enhancing the release of nitric oxide from the endothelium. Among such therapies, arginine treatment remains the most studied. Since the 1990s, it has been shown that arginine improves endothelial function in patients with hypercholesterolemia and hypertension, and has potential roles in diabetes (Siasos G, Tousoulis D, Antoniades C et al. Arginine, the substrate for NO synthesis: an alternative treatment for premature atherosclerosis? Int J Cardiol. 2007;116(3):300-308). This amino acid also improves endothelial function in patients with coronary artery disease and dilates human epicardial atheromatous coronary arteries (Tousoulis D, Böger RH, Antoniades C et al. Mechanisms of disease: L-arginine in coronary atherosclerosis–a clinical perspective. Nat Clin Pract Cardiovasc Med. 2007;4(5):274-283).
The effects of dietary or supplemental arginine on endothelial function were observed not only in patients (i.e, Bednarz B, Chamiec T, Maciejewski P et al. Kardiol. Pol. 2005;62:421-426 and Clarkson P1, Adams MR, Powe AJ et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest. 1996;97(8):1989-1994), but also in healthy humans. A single oral dose of 6 g arginine given to healthy people led to a significant vasodilator effect and concomitantly increased the plasma levels of both arginine itself and NO (Bode-Boger SM, Boger RH, Galland A et al. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol. 1998;46(5):489-497). The positive effect of arginine appears age-independent, since it was observed in both young and elderly humans (Bode-Böger SM, Muke J, Surdacki A et al. Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med. 2003;8(2):77-81).
Understandably, the effectiveness of arginine was more pronounced in situations associated with compromised cardiovascular function(s) in otherwise healthy people. Among such situations, cigarette smoking is perhaps most relevant. In smokers, arginine, but not vitamin C, reversed the deleterious effects of smoking on vasodilation (Adams MR, Jessup W, Celermajer DS. Cigarette smoking is associated with increased human monocyte adhesion to endothelial cells: reversibility with oral L-arginine but not vitamin C. J Am Coll Cardiol. 1997;29(3):491-497). From a practical perspective of the supplemental use of arginine, it is noteworthy that the vascular functions of arginine are correlated to its circulating levels in the blood, which is a positive indicator of oral arginine treatment efficacy.
A question emerged whether traditionally recommended physical exercise or nutraceutical treatments (mainly arginine-based treatments) are more effective for improving endothelial functions. This question was addressed in 40 patients with chronic heart failure, and it was shown that dietary arginine supplementation, as well as regular physical exercise, improved endothelium-dependent vasodilation to a similar extent. Both interventions together seemed to produce additive effects with respect to endothelium-dependent vasodilation (Hambrecht R, Hilbrich L, Erbs S et al. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J Am Coll Cardiol. 2000;35(3):706-713). In line with this clinical observation, animal studies indicated that arginine increased muscle capillary blood flow even if animals were not performing exercise.
Supplementation with arginine might provide additional blood flow at rest and during exercise and improve exercise capacity, and thus, additively enhance the positive effects of exercise on heart function (Ohta F, Takagi T, Sato H et al., Low-dose L-arginine administration increases microperfusion of hindlimb muscle without affecting blood pressure in rats. Proc Natl Acad Sci U S A. 2007;104(4):1407-1411).
Finally, it is worth noting that arginine is a very safe amino acid, and oral doses up to 15 – 20 g per day are well tolerated.
アルギニンの投与により、死産の割合が23％減少したのに対して（P < 0.05）、生きて生まれる仔ヒツジの割合は59％高まった（P=0.05）。 アルギニンの静脈投与により、4つ仔の出生時の体重を23％増加させた（P<0.05）が、母親の体重には影響はなかった。妊娠状態の改善は、アルギニン、オルニチン、システイン、プロリンの血漿中濃度の上昇やアンモニアおよびβ-ヒドロキシ酪酸塩の血中濃度の減少にも関連がある。 こうした目新しい結果は、多胎妊娠しているヒツジにアルギニンを非経口投与することで胎児死亡率や発育遅延が改善されることを示す。 本研究成果は、多胎妊娠しているヒトの女性において胎児の成長率及び生存率向上を目的とするアルギニンを使用した臨床試験の根拠の一つになっている。
Cystine and cysteine modulate immune system
Cystine is an amino acid composed from two cysteine molecules connected by a sulfuric bond. The amino acid cysteine, as such, is one of the direct precursors of glutathione, a key antioxidant and immune-supporting molecule, and its supply is considered to be a rate-limiting factor in glutathione synthesis. The small peptide glutathione is synthetized from cysteine and glutamate.
Several ways of providing those two amino acids have been explored to keep glutathione availability high during situations when immune system should be up-regulated (for example in common cold). Since orally-provided glutamate is mostly metabolized in the gut; theanine (an amino acid-like molecule derived from green tea) has been used as a means to increase circulating glutamate levels. In initial rodent experiments, a combination of cystine and theanine increased glutathione synthesis and enhanced resistance to influenza infection (www.ncbi.nlm.nih.gov/pubmed/19940390 ). In elderly humans, co-administration of cystine and theanine before influenza vaccination improved the immune response to the vaccine in those subjects who were characterized by low serum total protein and hemoglobin and who were therefore especially vulnerable o infections (www.ncbi.nlm.nih.gov/pubmed/19149835). Comparably, in younger people who were subjected to long-distance run, the combination of cysteine and theanine efficiently attenuated the reduction in lymphocyte count and overall drop in immune reactivity invariably induced by intense endurance exercise (www.ncbi.nlm.nih.gov/pubmed/20525371). Some of those positive results could be perhaps explained as a secondary consequence of glutathione stimulation, as hypothesized recently by Dr. Kurihara and colleagues (www.ncbi.nlm.nih.gov/pubmed/24312747 ).
While more detailed analysis of the action mechanism is necessary, the amino acid cysteine, in a combination with theanine, may lead to improved vaccination efficacy in older people with reduced immunological functions. Also, it may serve as a dietary supplement for those who wish to maintain their physical condition throughout the year or to athletes in endurance disciplines. Attention to appropriate dosing of cysteine is warranted.
グルタミンは経口摂取により体内に吸収され4)、その効果は動物およびヒトでの試験で実証されています1,5,6)。ヒトの食物でのグルタミンの上限摂取量に関して、副作用を示す記録はほとんどありません（第7回 アミノ酸の食事による適量摂取の評価に関するICAASワークショップ）7）。グルタミンが成長ホルモンの分泌を刺激し、免疫系を高める効果を検証する成人を対象とした臨床試験によると、必要なグルタミンの量は1日当たり2－30gとされています1,6,8,9)。本報告ではグルタミン摂取による問題のある副作用の記録はありません。最近提唱されているOSL（Observed Safe level：安全性が確認されている一日摂取量）では、グルタミンのOSLは14g/日です10)。ラットを用いた急性経口毒性試験では、グルタミンの半数致死量（LD50値）は16g/kg（体重）以上です11)。
- Welbourne TC.Increased plasma bicarbonate and growth hormone after an oral glutamine load.American Journal of Clinical Nutrition.61(5):1058-61, 1995
- In-house data at Kyowa Hakko Kogyo Co., Ltd.
- Newsholme EA.Crabtree B. Ardawi MS.Glutamine metabolism in lymphocytes: its biochemical, physiolog-ical and clinical importance.Quarterly Journal of Experimental Physiology.70(4):473-89, 1985
- Ziegler TR.Benfell K. Smith RJ.Young LS.Brown E. Ferrari-Baliviera E. Lowe DK.Wilmore DW.Safety and metabolic effects of L-glutamine administration in humans.Jpen:Journal of Parenteral & Enteral Nutrition.14(4 Suppl):137S-46S, 1990
- Moriguchi S. Miwa H. Kishino Y. Glutamine supplementation prevents the decrease of mitogen response after a treadmill exercise in rats.Journal of Nutritional Science & Vitaminology.41(1):115-25, 1995
- Castell LM.Poortmans JR.Newsholme EA.Does glutamine have a role in reducing infections in athletes? European Journal of Applied Physiology & Occupational Physiology.73(5):488-90, 1996
- The 7th Workshop on the Assessment of Adequate Intake of Dietary Amino Acids.The Journal of Nutrition.138, Supplement, 2008.
- Yoshida S. Matsui M. Shirouzu Y. Fujita H. Yamana H. Shirouzu K. Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer.Annals of Surgery.227(4):485-91, 1998
- Stehle P. Zander J. Mertes N. Albers S. Puchstein C. Lawin P. Furst P. Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery.Lancet.1(8632):231-3, 1989
- Shao A. Hathcock JN.Risk assessment for the amino acids taurine, L-glutamine and L-arginine.Regulatory Toxicollogy & Pharmacology.50(3):376-99, 2008
- Amino Acid Data Book.Japanese Society for Amino Acid Sciences.2010
Glutamine and Immune System Support
Glutamine is considered an essential amino acid during stress and critical illness which means that the human body cannot synthetize enough of glutamine to satisfy the needs or rapidly proliferating cells of the immune system, especially in the gut. Partial glutamine deficiency is considered an independent risk factor of mortality in patients after a major operation (which is of course a major stress to the body).
Even in otherwise healthy people in situations of extreme stress, such as heavy exercise, viral or bacterial infections, the concentration of glutamine in the blood diminishes. In many athletes, both recreational and professional, this decrease occurs concomitantly with relatively transient immune-depression and might be worsened by mild infections which are often untreated (Field CJ et al. Glutamine and arginine: immunonutrients for improved health. Med Sci Sports Exerc. 2000;32(7S):S377-S388). Since glutamine is used as a fuel by rapidly proliferating cells of the immune system, oral intake of glutamine has been seen to have a beneficial effect on gut function, on morbidity and mortality, and on some aspects of immune cell function in clinical studies (Castell L., Glutamine supplementation in vitro and in vivo, in exercise and in immune-depression. Sports Med. 2003;33(5):323-345). It has also been seen to decrease the self-reported incidence of illness, probably through its action on neutrophils (Rohde T et al. The immune system and serum glutamine during a triathlon. Eur J Appl Physiol Occup Physiol. 1996;74(5):428-434). Another possible mode of action is a glutamine-induced increase of the lymphocyte count and concomitant decrease in lipid peroxidation (Cavalcante AA et al. Enteral nutrition supplemented with L-glutamine in patients with systemic inflammatory response syndrome due to pulmonary infection. Nutrition. 2012;28(4):397-402). Finally, it also needs to be noted that glutamine is one of the three amino acids involved in glutathione synthesis and it serves as a precursor for the production of arginine through the citrulline-arginine pathway. Those pathways may be contributing to overall beneficial effects of glutamine supplementation. Glutathione, an important intracellular antioxidant and hepatic detoxifier may also be one of the reasons of protective effects of glutamine in stress and immune-depression.
Most of the clinical knowledge on glutamine effects in stress and strenuous exercise are derived from its medical applications after infections and/or in difficult post-operative states (García-de-Lorenzo A et al. Clinical evidence for enteral nutritional support with glutamine: a systematic review. Nutrition. 2003;19(9):805-811). In those situations, glutamine has been applied at relatively high doses of 20 – 30 gram and reportedly improved survival of the patients and lowered both time and costs of medical treatments (Gianotti L et al. Oral glutamine decreases bacterial translocation and improves survival in experimental gut-origin sepsis. JPEN J Parenter Enteral Nutr. 1995;19(1):69-74 and Al Balushi RM et al. The clinical role of glutamine supplementation in patients with multiple trauma: a narrative review. Anaesth Intensive Care. 2013;41(1):24-34).
Stresses of daily life are much less damaging that the life-threatening post-operative states, yet the neuro-endocrine-immune responses are qualitatively similar. Thus, as already mentioned athletes and otherwise healthy subjects under stress, clearly benefit from provision of glutamine due to stimulated immune system and enhanced functionality of immune cells in the gut (Akagi R et al., Glutamine protects intestinal barrier function of colon epithelial cells from ethanol by modulating Hsp70 expression. Pharmacology. 2013;91(1-2):104-111). Such an effect invariably leads to lower rates of infections and contributes to maintaining the health of the mucosa (inner wall) of the gastrointestinal tract.
Finally, healthy adults take app. 5 – 9 gram glutamine from daily diet and supplemental glutamine is considered safe when used in accordance with proper dosing.
Glutamine importance for human health; recent findings and advances
Amino acids are the building blocks of proteins and they have numerous proven roles in the human body, including organ functionality, storage of nutrients, cell structure of muscular tissue and many more. Lack of amino acids often leads to a series of problematic health effects, especially in specific population groups such as older people and hard training athletes. Specific amino acids are correlated to several of these effects and it is commonly advised to be also taken by the people in question in the form of nutritional supplements.
One such amino acid, with proven correlation to health symptoms, is glutamine. Glutamine’s most important role in the human body is the stabilization and tuning of the immune system. As a consequence, people with appropriate glutamine intake tend to exhibit good health even at harsh living conditions. Other secondary glutamine related phenomena are the optimization of sleep behavior, calmness of mind, and reduction of anxiety.
Relevant research works have suggested that there is a relation between glutamine content and free radicals, especially in times of high stress; the lower the glutamine content, the higher the free radicals content. Free radicals are greatly active species that exist due to homolytic division of chemical species that results in two parts left with just one electron. The presence of just one electron makes free radicals always trying to ‘attack’ other molecules [propagation stage] until the process is completed by combination of two free radicals [termination stage]. In biological systems, these attacks result to cells being damaged severely and their functionality and efficiency being significantly lowered. Keeping in mind that glutamine is the most important single energy carrier, low content in combination with free radicals uncontrolled action lead to increased anxiety and functionality control loss.
A three species balance governs peace of human mind; glutamine – glutamic acid – gamma amino butyric acid. Between the two first, a chemical equilibrium occurs. On the other hand, glutamine acts like a catalyst for the production of gamma amino butyric acid [GABA]. GABA is a brain ‘insulator’, an inhibitory neurotransmitter. Sufficient quantities of GABA ensure minimization of unwanted signals and interactions in the brain, resulting to calmness, enhanced concentration, peace of mind and greater quality of sleep. Relevant studies have also correlated GABA actions with treatment of depression.
Sleep quality depends heavily on glutamine, as well as on other amino acids such as ornithine and arginine. All three of them act as detoxifiers of ammonia, especially in the liver. Ammonia comes from the decomposition of large protein quantities in the body and its high levels have been correlated with loss of sleep and liver intoxication. These detoxifiers transform ammonia into urea, offering a great enhancement of sleep quality and mental clearness. Other amino acids and vitamins have been correlated with this effect by several studies; most of them include B6 and B12 vitamins.
Nutritional supplements industry is expected to focus more intensely of glutamine containing formulations. Use of recent findings support the multifunctional effect on human health and on specific biological processes as discussed here. Combination with other amino acids seems to be prominent as well.
The most plentiful amino acid
Non-essential amino acid glutamate appears to be on the cross-roads of all key metabolic process; it is synthetized in our organs and present in our food. We do not really know what makes glutamate so special. But, since it is a part of every single protein, nature has selected glutamate to become the signal molecule for protein digestion (www.ncbi.nlm.nih.gov/pubmed/23463402).
Due to importance of protein for both growth and maintenance, mammals have developed ability to sense and to like glutamate taste (umami) and also to recognize it after the digestion – in the intestines (www.ncbi.nlm.nih.gov/pubmed/26247011). Already our first food experience, mother milk, is very rich in glutamate (and infants like it, http://www.ncbi.nlm.nih.gov/pubmed/23660363 ). This is most linked to glutamate’s protective role against infections of the intestinal tract. Glutamate is so precious for all higher mammals that we have perfected compartmentalization of its uses. This means that glutamate from one bodily “pool” (for example brain) is not affected by glutamate from other “pools” (periphery) and vice versa.
Considering all the above-written; it is not surprising that as soon as production technologies were in place during early 20th century, inventive people came to an idea to purify glutamate, make it stable, dry, easy-to-use … and sell it as a taste substance. It was much easier to use purified glutamate to enhance flavor than to use various glutamate-rich savory sauces, cheeses, yeast extracts or vegetables. Of course, a similar point can be made when comparing the use of salt (sodium chloride) and that of anchovies. Sodium chloride is cheaper, easier to use and much more stable. The key difference is that we call “salt” salt and not “sodium chloride”, and also that pure salt has 1,000s years of history, while glutamate has only 100.
Since the most stable form of glutamate turned to be the sodium form (MSG); it is the glutamate most of us know. It had been used widely for some 60 years until someone speculated in late 1969 that MSG might be the reason for headache-like feelings after eating unknown foods. Because scientific knowledge on amino acids was practically zero and because late 1960 was the first time when people started to question modern food industry, the accusations against MSG found a fertile ground.
Between 1970 and 2015, MSG has been the most widely studied food ingredient in the human history. All the toxicological science which was thrown at the substance only reiterated its safety. Even better, sometime around year 2000, scientists documented that there were glutamate receptors on our tongues, which proved beyond doubt that MSG had a long evolutionary role in food digestion. Other projects have illustrated benefits of MSG, such as stimulation of intestinal contraction (www.ncbi.nlm.nih.gov/pubmed/10736365) or salivation – both very important for proper digestion. Scientifically speaking, there is very little to add to the impressive story of food-added glutamates. It took 45 years; but MSG has been shown to be not only a safe but also a beneficial food substance.
Finally, glutamate is not alone among those amino acids that can be used as flavors. Since free amino acids have taste properties, fourteen of them have been recognized as flavor substances in the USA and elsewhere. Luckily for them; none of those amino acids have reached notoriety of that single form of glutamate known as MSG.
L-セリンは、タンパク質を構成する非必須アミノ酸の一種で、グリシン、システイン、フォスファチジルセリン、および、スフィンゴ脂質などの前駆体として知られている。L-セリンは、大豆、などの様々な食品中に、タンパク質を構成する成分または遊離型アミノ酸として存在する。日本人のL-セリンの平均摂取量は、男性3.81g/日、女性3.24g/日と報告されている（Kato et al., Jap. Soc. Nutri. Diet. 71 (2013)）。近年、生理活性を目的としてサプリメントなどに用いられており、脳機能 （Shigemi et al., Neurosci Lett. 468 (2010))、睡眠（Ito et al., Springer Plus 456 (2014)）や皮膚などへの影響が報告されている。
L-セリンの安全性に関する以下の報告がある。非臨床安全性試験では、ラットにL-セリンを 500、1,500、および、3,000 mg/kg/日の用量で13週間の反復投与による毒性試験が実施された。本試験結果から、L-セリンの無毒性量は、3,000 mg/kg/日と報告（Kaneko et al., Food Chem Toxicol. 47 (2009))されている。さらに、ラットにL-セリンを0.06、0.5、1.5、および、5.0 %混餌の用量で90日間の反復投与による毒性試験が実施された。本試験結果から、L-セリンの無毒性量は、5.0 %混餌 （雄：2,765 mg/kg/日、雌：2,905 mg/kg/日）と報告 (Tada et al., J Toxicol Pathol 23 (2010))されている。ヒトでの安全性に関わる試験では、健康な成人での報告ではないが、筋萎縮性側索硬化症（ALS）患者20名にL-セリン0.5、2.5、7.5、および、15 g/日の投与量における6ヶ月間の試験が実施された。本試験の結果から、L-セリンの15g/日までの投与量で有害事象は観察されないことが報告（Levine et al., Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.18 (2017)）されている。
Tyrosine for your thoughts
“You are what you eat”, the wisdom of ancient worlds would be even more accurate if one tried to narrow the scope of eating to “eating amino acids”. Among others, you need to ingest essential amino acids to stay alive; you need to eat tryptophan to be in positive mood, proline to keep healthy skin or glutamate to preserve your intestines moving (www.ncbi.nlm.nih.gov/pubmed/24251696). This list would be very long…
It sounds too simple, but in this case “simple” is not naïve. Let’s look at what science says. In a recent study (www.ncbi.nlm.nih.gov/pubmed/25257259), clinicians investigated whether creativity was promoted by supplementing diet with the non-essential amino acid tyrosine. The biochemical reason was pretty straightforward; tyrosine is the precursor of brain neurotransmitter dopamine, which is assumed to underline creativity and dietary intake of tyrosine correlates with much of tyrosine actually finishes in your brain. Scientists found evidence that tyrosine promoted deep thinking which required substantial cognitive control, suggesting that tyrosine may facilitate creative operations. Wow, can we still categorize tyrosine as a “non-essential amino acid”?
This line of thinking is not even new. Among others, you may have a look at the following 40-year-old review article focused on dietary control of some brain neurotransmitters (www.ncbi.nlm.nih.gov/pubmed/1093382). A few researchers in the four decades demonstrated positive impact of supplemental tyrosine on various aspects of memory performance, mostly in situations when the cognition was compromised by outside factors, such as sleep deprivation www.ncbi.nlm.nih.gov/pubmed/12887140 or stress. For example, one human test showed that exposure to very cold weather degraded cognitive performance (that sounds logical since a freezing body must concentrate on more pressing issues than cognitive brilliance) and supplementation with tyrosine significantly normalized it (www.ncbi.nlm.nih.gov/pubmed/17585971).
To strengthen experimental evidence, researchers tried also to look at cognitive effects of tyrosine depletion (i.e., www.ncbi.nlm.nih.gov/pubmed/16163534), reversing the above logic and expecting a drop in memory performance. Interestingly, they found only minor impact on spatial working memory and planning accuracy. Well, it seems the human brain is truly a complicated “machine” and a removal of one “memory fuel”, in a form of the amino acid tyrosine, does not lead to a complete break-down of higher cognitive functions. But, to be on the save side, eat foods rich in fish, turkey, egg white or simple try high quality tyrosine supplements.
L-オルニチンは、タンパク質の構成に寄与しないアミノ酸の一種で、遊離型アミノ酸として存在する。 L-オルニチンは、生体では有害なアンモニアを尿素に変換する尿素回路を構成する物質の一つである。 L-オルニチン(mg/100g)は、シジミ（159.9）、米（26）、キハダマグロ（1.9-7.2）、緑茶（2-15）、および、小麦粉パン（0.4）などの食品に含まれる（Uchisawa et al., Biotech. Biochem. 68 (2004), Cagampang et al., Cereal Chemists. 48 (1971）, Antoine et al., Food Chem. & Toxico. 66 (2001), Ohtsuki et al., Agric. Biol. Chem., 51 (1987), Prieto et al., J. Chromato. Sci. 28 (1990）)。近年、生理活性を目的としてサプリメントなどに用いられており、肝臓機能改善（Müting et al., Amino Acids 3 (1992)), 睡眠改善（Horiuchi et al., Nutr Res 3 (2013), Miyake et al., Nutr J, 3 (2014))などが報告されている。
L-オルニチンの安全性に関する以下の報告がある。非臨床試験では、ラットにL-オルニチンを1.25、2.5、および、5.0 %混餌の条件で13週間の反復投与による毒性試験が実施された。本試験の結果から、L-オルニチンの無毒性量は、5.0 %混餌（雄：3,444 mg/kg/日、雌：3,985 mg/kg/日）と報告(Ishida et al., Reg. Toxico. Pharm. 67 (2013))されている。ヒトでの安全性に関わる試験では、L-オルニチン-α-ケトグルタル酸塩 10 g（L-オルニチンとして6.4g、L-オルニチン塩酸塩として8g相当）/日を2ヶ月摂取させた試験が実施された。本試験の結果から、L-オルニチン-α-ケトグルタル酸塩 10 g/日の投与による因果関係のある有害作用は認められていない。なお、胃腸症状による脱落例があったが、L-オルニチン摂取との因果関係は報告されていない（Brocker et al., Age and ageing 23 (1994)）。
L-シトルリンは、タンパク質の構成に寄与しないアミノ酸の一種で、遊離型アミノ酸として存在する。L-シトルリンは、生体では有害なアンモニアを尿素に変換する尿素回路を構成する物質の一つである。1980年代に、L-シトルリンの摂取によるL-アルギニンを介した一酸化窒素（NO）産生に関する知見が見出された。L-シトルリン (mg/100g) は、スイカ（180）、ヘチマ（57）、メロン（50）、冬瓜（18）、および、キュウリ（9.6）などの食品に含まれることが報告（林, 化学と生物46 (2008))されている。近年、生理活性を目的としてサプリメントなどに用いられており、疲労回復（Bendahan et al., Br J Sports Med. 36 (2002)）、運動パフォーマンスの向上（Perez-Guisado et al., J Strength Cond Res. 24 (2010）)、および、むくみの解消（森田ら. 薬理と治療 40 (2012)）などが報告されている。
L-シトルリンの安全性に関する以下の報告がある。非臨床試験では、ラットにL-シトルリンを2,000 ｍg/kg/日の用量で6週間の反復投与による毒性試験が実施された。本試験の結果から、L-シトルリン2,000 ｍg/kg/日の投与量で有害事象は観察されないことが報告(Morita et al., Fund Toxico. Pharm. 67 (2017))されている。ヒトでの安全性に関わる試験では、健康な成人8名にL-シトルリン2、5、10、および、15 g/日の投与量における単回投与試験が実施された。本試験の結果から、L-シトルリン15g/日までの投与量で有害事象は観察されないことが報告 （Moinard et al., Brit. J. Nutri.99 (2008)）されている。また、健康な成人男性17名にL-シトルリンを、6ｇ/日の投与量で4週間の反復投与試験が実施された。本試験の結果から、L-シトルリン6g/日の投与量で有害事象は観察されないことが報告（Figueroa et al., Amer. J. Hyper.23 (2009)）されている。