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Clinical Chemistry Laboratory, Hôtel-Dieu Hospital – AP-HP and Laboratory of Biological Nutrition EA 2498, Pharmacy Faculty, Paris Descartes University, Paris, France
3 To whom correspondence should be addressed. E-mail: luc.cynober{at}htd.ap-hop-paris.fr
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • amino acids • sulfur amino acids • safety • aging
Amino acid requirements. Over the years, a large amount of research has led to the definition of amino acid requirements, although there are still uncertainties resulting from methodologic problems in assessment and variability according to protein source as well as a number of other factors (1).
Recent advances in the nutritional sciences indicate that, beyond basic nutritional requirements, some amino acids have specific functions [i.e., the control of protein synthesis by leucine (2), the regulation of immunity by arginine (3)]. Therefore, it is not surprising that dietary supplementation with some specific AAs may be useful in certain situations. As a result, it is necessary to determine the functional consequences of intakes that fall outside "normal" requirements and how best to predict both the beneficial effects that result from the correction of a deficiency and the potentially adverse effects that may arise at high dietary and/or supplemental intakes under various dietary, "host" and environmental conditions (4).
What is the International Council on Amino Acid Science? The International Council on Amino Acid Science (ICAAS)4 is a scientific organization promoting research on amino acids in clinical nutrition, with a special interest in determining the upper limit of safe intake.
One of the major actions led by the ICAAS is the organization of a series of "Amino Acid Assessment Workshops" (AAAWs).
The purpose of the AAAWs: Background. Around 3.4% of the U.S. population uses AA supplements, 62% of them on a daily basis (1). These figures are different in other populations, depending on lifestyle and country-specific regulations.
However, there is a lack of information on the potential adverse effects and the pathophysiological consequences arising from an excessive intake of individual AAs or mixtures in human populations. Therefore, it is necessary to establish a sound scientific basis for evaluating AA efficacy and safety under various conditions of use (i.e., higher than usual) as part of a health promotion initiative (1).
The goal of the ICAAS (via the AAAWs) is to bring together experts in amino acid nutrition, metabolism, toxicology, regulation issues and policy with the aim of establishing a paradigm for the characterization of risks associated with specific intakes of AAs by humans. The AAAWs represent a means for establishing continuing scientific dialog between experts from various medical and scientific fields.
The first AAAW held in Tokyo (2001). The meeting addressed general questions on AAs: 1) What are their roles? 2) What are their function(s), and what is the relation between AA metabolism and function, particularly in the brain? 3) What are the adverse effects of excessive intakes (e.g., imbalance, antagonism, toxicity), and what mechanisms are involved? Obviously, in evaluating toxicity data for nutrients, it is essential to determine whether any observed change is an adverse event or simply a nonpathological and reversible physiological adaptation. 4) How can we predict or anticipate these effects and mechanisms? 5) How do genetic and other factors influence responses to amino acid intakes? 6) What aspects of the risk assessment paradigm used for foreign chemicals is applicable to AAs (e.g., definition of no observed adverse effect level: NOAEL)?
Different AAs have very different metabolic fates, although there is a great deal of metabolic and functional interaction between AAs. Therefore, a single approach to the assessment of AAs is not possible. This was nicely demonstrated by Young (1), who reported that the addition of high methionine levels to a casein-based diet in growing rats results in an immediate loss of body weight, whereas the further addition of glycine to this high-methionine casein diet prevented the weight loss.
The second AAAW held in Hawaii (2002). This meeting focused on how recent advances in biology might help to better understand the mechanisms involved and improve the ability to predict responses to altered intakes of AAs and their safety (1). A number of potentially useful methods were considered, but, unfortunately, they have so far been underused in the risk assessment of AAs. One example is amino acid tracer kinetics, application of which to establish upper safe intake levels has been essentially nonexistent (5). Clearly, the study of genome, proteome, and metabolome in organs and tissues is a key step in defining suitable biomarkers (i.e., how to define and identify the molecular signatures of a pathological response to AA intake) for use in risk assessment. The great advantage of metabolomics over the other "omics" is that it can be applied to in vivo studies in humans and to monitoring changes in animals over relevant dose ranges (6).
The decision as to which organs or tissues to focus on was the subject of major discussion during this AAAW. The brain (and thus, behavior) and the kidney emerged as major targets (7).
This workshop also considered the design of possible animal experiments. Which species? What dosages? What duration? Which surrogate biomarkers (of exposure, response, susceptibility)? These items were also discussed at AAAW1 and AAAW3 because a major objective of this workshop series is to link data between animals and humans.
During this meeting, it was clearly pointed out that amino acids are quite different from drugs and xenobiotics in that the amino acids are endogenous metabolites needed by the body, whereas foreign chemicals are handled differently because the body's primary goal is to detoxify them. Hence, conventional risk assessment techniques probably cannot be directly applied to amino acids (7).
The first and second AAAWs concluded with the need to develop reliable functional markers of adequate and excess AA intakes. Useful markers will need to show the following characteristics (1): be accessible for measurement, be present in body fluids or cells that can be sampled or imaged in some way, be present in a form and quantity that can be measured objectively and reproducibly, and reflect changes in the target tissue or fluid that have a direct impact on health.
There is currently no single biomarker that can fulfill all these criteria and therefore "upstream tools" (e.g., the microarray approach) will need to be combined with "downstream tools" (e.g., dynamic assessment of plasma AA variations) (8,9).
The third AAAW held in Nice (2003). This meeting focused on the intakes of AAs needed to meet physiological and specific requirements in certain situations, e.g., infants, aging, sports training, or disease (parenteral nutrition) and to the dietary factors influencing AA metabolism and effects (4). The underlying concept explored at the meeting was that the upper limit of the safe range of intake may vary according to physiological or pathological state. Both exercise and aging generate specific AA requirements (10), and the combination may affect the upper limit of safe intake in a way that is not predictable.
In addition, the discussions confirmed that application of the risk assessment approach used for nonnutrients would be only partially workable for nutrients such as AAs (4). For example, the application of an uncertainty factor of 100 to data obtained in rodents to allow for species differences and human variability (11) would result in the need to perform toxicity studies on single amino acids at dietary levels that would result in profound nutritional imbalances. Hence, in contrast to the study of safe intake of nonnutrients, studies on AAs might require a parallel control group with a burden of "nonspecific" nitrogen equivalent to that of the animals given the single AA (12). However, the problem is selecting a suitable source of "nonspecific nitrogen," because urea or ammonia cannot seriously be envisaged as a control. The nutrition literature shows that a single AA (e.g., glycine), a combination of free AAs (4, 6, or more), protein hydrolysate or whole protein had been used previously, but there are few published studies (13) assessing the effects in such controls.
At this meeting, the issue of experimental models was again raised in several lectures, including a discussion (12) on the problems caused by palatability changes at high dietary concentrations; the 22 AAs include some that are essentially tasteless, some that are bitter, some that are salty, and others that are sweet. A benefit of the avian model is that chickens have very little perception of taste, so this important confounding factor is eliminated (12), although the problem of extrapolation to humans is increased.
The fourth AAAW held in Kobe (2004). This meeting was a change of approach in that it focused the issues discussed in AAAWs 1 to 3 onto a particular group of AAs, the branched-chain amino acids (BCAAs). BCAAs were chosen because they have numerous regulatory functions, relatively simple metabolism, are involved in inherited diseases, and because there are claims for their beneficial use at very high intakes in specific situations (e.g., sports training).
This group of AAs produce very few adverse effects (after acute or chronic administration) (14) so that there was only limited potential to explore the applicability of the outcomes of previous workshops. This workshop provided valuable information, in particular with regard to brain metabolism [i.e., lessons from maple syrup urine disease (15)] and function (16), gender differences (e.g., female subjects seem more sensitive to excessive valine than male), and interactions with other nutrients (i.e., glucose), which may be involved in some disease states (e.g., diabetes type 2). Furthermore, the species selection for suitable studies was identified as a problem for BCAAs because the tissue expression of the initial metabolizing enzymes (i.e., AACR transaminase and branched-chain keto acid dehydrogenase) is different in rodents and humans (17). An additional problem is that commercially available healthcare products contain all 3 BCAAs, and administration of large amounts of the 3 BCAAs complicates the issue because they compete for cell transport and metabolism.
There is certainly a potential interest of leucine supplementation in elderly people presenting both a splanchnic sequestration of this AA (18) and a resistance to stimulation of muscle protein synthesis (19). However, there is a lack of interventional studies showing that leucine diet supplementation can be efficient in preventing or slowing down sarcopenia.
The fifth AAAW (Los Angeles, 2005). The most recent workshop focused on sulfur AAs (SAAs). This group of AAs was selected for several reasons: 1) Unlike the BCAAs, the SAAs, particularly methionine, are toxic at high intakes and are suitable for consideration of the best approach to risk assessment. 2) SAAs illustrate the potential importance of AAs in pathophysiology (e.g., cardiovascular disease, stroke) because it is well known that plasma homocysteine (HCys) concentrations during fasting are higher than normal in patients with vascular disease (20). The role of HCys may be indirect, i.e., related to asymmetric dimethylarginine (ADMA), which may be a key mediator in the link between hyperhomocysteinemia and endothelial dysfunction (21). 3) Possible biomarkers of excessive intake need to be identified: the fact that methionine load can induce hyperhomocysteinemia (22) strongly supports the idea that HCys may be a strong candidate surrogate marker of excessive SAA intake. There is other evidence [see (22) for details] that HCys is a marker rather than the cause of various diseases in which HCys levels are high, including various diseases affecting elderly populations (e.g., hip fracture, cognitive deficits, cardiac failure) (21). 4) Non-AA cofactors (such as vitamins B-6, B-9, and B-12) are important in SAA disposal and effects (20). 5) Interorgan amino acid transport is important in defining specific targets (e.g., taurine in hair bulb) and in providing the right AA at the right time. 6) Safety assessment (hazard identification, hazard characterization, exposure assessment, and risk characterization) appears to be a major challenge in the case of SAAs. A high intake of cysteine or methionine may be associated with severe deleterious effects, which may differ between humans and animal models, again raising the problem of extrapolation of animal data to humans.
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FOOTNOTES |
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2 This paper is dedicated to Prof. Vernon R. Young, whose vision created this series of workshops, and who chaired with talent the first 3.
4 Abbreviations used: AA, amino acid; AAAW, amino acid assessment workshop; ADMA, asymmetric dimethylarginine; BCAA, branched-chain amino acid; HCys, homocysteine; ICAAS, International Council on Amino Acid Science, NOAEL, no observed adverse effect level; SAA, sulfur amino acid.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. Young VR. Introduction to the 2nd amino acid assessment workshop. J Nutr. 2003;133(Suppl):2015S–20S.
2. Kimball SR, Jefferson LS. Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. J Nutr. 2006;136(Suppl):227S–31S.
3. Morris SM, Jr. Recent advances in arginine metabolism. Curr Opin Clin Nutr Metab Care. 2004;7:45–51.[Medline]
4. Young VR. Introduction to the 3rd amino acid assessment workshop. J Nutr. 2004;134(Suppl):1555S–7S.
5. Bier DM. Amino acid pharmacokinetics and safety assessment. J Nutr. 2003;133(Suppl):2034S–9S.
6. Renwick AG. The safety testing of amino acids. J Nutr. 2003;133(Suppl):2031S–3S.
7. Cynober L, Young VR. General discussion at 2nd amino acid assessment workshop. J Nutr. 2003;133(Suppl):2101S–7S.
8. Kato H, Kimura T. Evaluation of the effects of the dietary intake of proteins and amino acids by DNA micro array technology. J Nutr. 2003;133(Suppl):2073S–8S.
9. Cynober L. Plasma amino acid levels with a note on membrane transport: characteristics, regulation and metabolic significance. Nutrition. 2002;18:761–6.[Medline]
10. Cynober L, Young VR. Discussion of sessions 1 and 2 at the 3rd amino acid assessment workshop. J Nutr. 2004;134(Suppl):1597S–9S.
11. Renwick AG, Walker R. The fourth workshop on the assessment of adequate intake of dietary amino acids: general discussion of session 3 and overall workshop discussion. J Nutr. 2005;135(Suppl):1602S–6S.
12. Cynober L, Young VR. General discussion at the 3rd amino acid assessment workshop. J Nutr. 2004;134(Suppl):1667S–72S.
13. Chambon-Savanovitch C, Felgines C, Farges MC, Raul F, Cézard JP, Davot P, Vasson MP, Cynober L. Comparative study of glycine, alanine or casein as inert nitrogen sources in endotoxemic rats. J Nutr. 1999;129:1866–70.
14. Baker DH. Tolerance for branched-chain amino acids in experimental animals and humans. J Nutr. 2005;135(Suppl):1585S–90S.
15. Mitsubuchi H, Owada M, Endo F. Markers associated with inborn errors of metabolism of branched-chain amino acids and their relevance to upper levels of intake in healthy people: an implication from clinical and molecular investigations on maple syrup urine disease. J Nutr. 2005;135(Suppl):1565S–70S.
16. Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005;135(Suppl):1539S–46S.
17. Brosnan JT. The fourth workshop on the assessment of adequate intake of dietary amino acids: general discussion of sessions 1 and 2. J Nutr. 2005;135(Suppl):1576S–9S.
18. Boirie Y. Gachon P. Beaufrère B. Splanchnic and whole-body leucine kinetics in young and elderly men. Am J Clin Nutr. 1997;65:489–95.
19. Fujita S, Volpi E. Amino acids and muscle loss with aging. J Nutr. 2006;136(Suppl):277S–80S.
20. Refsum H, Nurk E, Smith AD, Ueland PM, Gjesdal CG, Bjelland I, Tverdal A, Tell GS, Nygård O, Vollset SE. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr. 2006;136(Suppl):1731S–40S.
21. Teerlink T. Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance. Clin Chem Lab Med. 2005;43:1130–8.[Medline]
22. Selhub J. The many facets of hyperhomocysteinemia: studies from the Framingham Cohorts. J Nutr. 2006;136(Suppl):1726S–30S.
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