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European Journal of Clinical Nutrition (2006), 1–10& 2006 Nature Publishing Group All rights reserved 0954-3007/06 $30.00 Consensus meeting: monosodium glutamate – anupdate K Beyreuther1, HK Biesalski2, JD Fernstrom3, P Grimm4, WP Hammes5, U Heinemann6,O Kempski7, P Stehle8, H Steinhart9 and R Walker10 1ZMBH, University of Heidelberg, Germany; 2Department of Biological Chemistry and Nutrition (140a), University of Hohenheim,Germany; 3Departments of Psychiatry Pharmacology & Neuroscience and Center for Nutrition, University of Pittsburgh School ofMedicine, Pittsburg, USA; 4Nutrition Communication, Schurwaldstr. Schorndorf, Germany; 5Department of Food Technology andMicrobiology (150a), University of Hohenheim, Germany; 6Institute of Neurophysiology, Charite´ Berlin, Germany; 7Institute forNeurosurgical Pathophysiology, Johannes Gutenberg University Mainz, Germany; 8Department of Nutritional and Food Sciences –Nutrition Physiology, University of Bonn, Germany; 9Institute of Chemistry, Department of Food Chemistry, University of Hamburg,Germany and 10School of Biological Sciences, University of Surrey, UK Objective: Update of the Hohenheim consensus on monosodium glutamate from 1997: Summary and evaluation of recentknowledge with respect to physiology and safety of monosodium glutamate.
Design: Experts from a range of relevant disciplines received and considered a series of questions related to aspects of the topic.
Setting: University of Hohenheim, Stuttgart, Germany.
Method: The experts met and discussed the questions and arrived at a consensus.
Conclusion: Total intake of glutamate from food in European countries is generally stable and ranged from 5 to 12 g/day (free:ca. 1 g, protein-bound: ca. 10 g, added as flavor: ca. 0.4 g). L-Glutamate (GLU) from all sources is mainly used as energy fuel inenterocytes. A maximum intake of 16.000 mg/kg body weight is regarded as safe. The general use of glutamate salts(monosodium-L-glutamate and others) as food additive can, thus, be regarded as harmless for the whole population. Even inunphysiologically high doses GLU will not trespass into fetal circulation. Further research work should, however, be doneconcerning the effects of high doses of a bolus supply at presence of an impaired blood brain barrier function. In situations withdecreased appetite (e.g., elderly persons) palatability can be improved by low dose use of monosodium-L-glutamate.
European Journal of Clinical Nutrition advance online publication, 6 September 2006; doi:10.1038/sj.ejcn.1602526 Keywords: monosodium glutamate; CNS; breast milk; food safety; toxicology; human nutrition concensus conference considering the available new infor-mation with a special focus on safety aspects.
The 1997 Hohenheim consensus talk has dealt with aspectsof metabolic and safety aspects of monosodium glutamate(Biesalski et al., 1997). In the meantime, new data including results of an ‘International Symposium on Glutamate’(Fernstrom and Garattini, 2000) were published. Conse- quently, it was decided to update results of the 1997 To clarify that added monosodium-L-glutamate (MSG) and all other glutamate salts dissociate in aqueoussolutions and therefore are identical with free glutamic acid,only the term L-glutamate (GLU) should be used in the Correspondence: Professor P Stehle, Department of Nutritional and Food Sciences – Nutrition Physiology, University of Bonn, Endenicher Allee 11-13,Bonn D-53115, Germany.
GLU) but it appears as well in its free form in certain foods Guarantor: P Stehle.
Received 21 December 2005; revised 14 June 2006; accepted 6 July 2006 (free GLU). To this food derived GLU adds GLU salts (e.g., MSG) that are used as food enhancer in instant products to 1 g/day. As the consumption of tomatoes/tomato products such as soups, sauces or pizza. Presently, six additives are and cheese consistently increased in Germany during the last admitted in the European Union (EU): GLU (E620) and its years (German Nutrition Society 2004), a further increase in sodium (E621), potassium (E622), calcium (E623), ammo- free GLU intake from food can be expected.
nium (E624) and magnesium (E625) salt. These food Within the last couple of years, ‘low-carb diets’ were enhancers are not allowed to be added to milk, emulsified heavily promoted in western societies (Berkowitz, 2000).
fat and oil, pasta, cocoa/chocolate products and fruit juice.
Energy deficits due to low carbohydrate intake are generally Following the compulsory EU-food labeling law the use of compensated by a quantitatively higher protein, which may ‘enhancer’ has to be declared and the name or E-number of the salt has to be given. GLU salts dissociate in the neutral As food enhancer GLU is preferably used in form of area so that independent from origin and salt species free MSG. The concentration in convenience foods adds up to 0.1–0.8% of weight which is similar to the concentration ofnative free GLU in tomatoes or parmesan. Based onmeasured added GLU content of over 500 MSG-containing Estimated intake of GLU from natural sources (European diet, food items obtained from the grocery, Rhodes et al. (1991) calculated daily added GLU intake in the United Kingdom (UK). These are: whole population, 586 mg/day; households (as protein constituent or in free form in foods) can be buying foods in each category examined (likely to be calculated to about 10 g/day (range: 4.6–12 g/day). The use of maximum intake), 1560 mg/day; extreme users (97.5th new technologies in food processing (e.g., microwave percentile consumers), 2330 mg/day (likely to be maximum technology) does not influence native GLU content.
intake); children, 10–11 and 14–15 year, 1300 mg/day (if With respect to added GLU, only limited data are 40 kg body weight, 33 mg/kg/day; if 60 kg body weight, available. In EU countries the mean intake ranges from 0.3 22 mg/kg/day). If extreme consumption group weighs 70 kg to 0.5 g/day; in Asian countries people consume in average (adults), daily dose is about 30 mg/kg/day; if whole popula- 1.2–1.7 g/day. It is, however, to mention that the individual tion averages 50 kg (all ages), daily dose is about 12 mg/kg/ GLU intake from food additives shows broad variations; high consumers in Europe may reach up to 1 g/day, in Asian In Western societies, there is a general trend to an countries 4 g/day. Average intake in EU countries might only increased consumption of flavored convenience food. The- oretically, this change in behavior might lead to an increased The amount of GLU added to a specific product is limited GLU intake, which is used in these products as flavor. On the by the fact that increasing amounts of GLU will not increase other hand, the food industry steadily increases the number but decrease palatability. When specific nucleotides are of MSG-free products due to an enhanced reservation of the added as flavors to the products GLU content can be lowered consumer against food additives (Dillon, 1993). Conse- quently, overall intake of added GLU might not besignificantly altered.
With respect to the amount of protein bound In Asia, especially in Japan and Korea MSG and other GLU in a mixed diet only limited data are available. This is GLU salts are used more intensively than in Europe. In due to the fact that the amino-acid composition of a food these countries the intake of added GLU is estimated to protein is commonly assessed after acid hydrolysis and that 1.2–1.7 g/day (for details see Biesalski et al. (1997)). In a glutamine residues are decomposed to GLU during this highly seasoned restaurant meal, however, intake as high as process. In consequence, most of the amino-acid composi- 5000 mg or more may be possible (Yang et al., 1997).
tion data published only include the percentage of ‘GLX’ per100 g of protein/16 g of nitrogen reflecting the sum of GLUplus glutamine (Kuhn et al., 1996). With the assumption that What is the role of GLU in biochemical and metabolic processes? ca. 40% of GLX are native GLU residues, the amount of Most of GLU (up to 95%) derived from food protein bound GLU can be estimated to 4–12 g/100 g food (bound and added) is used as energy source by the protein (Anderson and Raiten, 1992). Considering an enterocytes of the intestinal mucosa.
average protein intake of 90 g/day for young adults (GermanNutrition Society 2004), GLU intake from intact protein In healthy adults, GLU can be endogenously synthesized in adequate amounts and, thus, is qualified as a In addition to bound GLU, some products like fresh fruits, nonessential (dispensable) amino acid (Fu vegetables and cheese contain various amounts of free 2004). The daily GLU turnover is calculated to about 48 g GLU (unprocessed potatoes: 50–80 mg/100 g, tomatoes: 200– (Garattini, 2000). GLU liberated from food protein is 300 mg/100 g, tomato products: up to 630 mg/100 g, long quantitatively absorbed from the lumen. Absorption kinetics matured cheese like Parmesan: up to 1200 mg/100 g). Based is influenced by the retention time in the stomach and the on a mixed diet, intake of free GLU can be presently estimated Studies over the last two decades have demonstrated 0.15–0.22 g/kg bw increased the maternal plasma level from extensive catabolism of nonessential amino acids in intest- a baseline value (50 mmol/l) to about 500–1000 mmol/l; GLU inal mucosa (Burrin and Reeds, 1997). In recent years, there concentration in fetal plasma was thereby, however, not has been growing recognition that catabolism also dom- affected. Only at the highest exposure (0.40 g/kg bw) inates the first-pass intestinal utilization of dietary essential amino acids (Stoll et al., 1998). The major objective of 2800 mmol/l there was an increase of the fetal plasma level current views of intestinal mucosal amino acid catabolism up to 440 mmol/l. A plasma level between 2000 and and its implications for protein and amino acid nutrition is 2500 mmol/l was identified as barrier for the GLU transfer the role of nonessential (indispensable) amino acids like to the fetus. It is therefore concluded that a transfer of GLU GLU. Current studies of Reeds et al. (2000) demonstrated from mother to fetus is highly unlikely even with the highest that GLU is the most important oxidative substrate for the intestinal mucosa. In addition, GLU (via glutamine) appearsto be a specific precursor for the amino acids arginine andproline as well as for the tripeptide glutathione by the small Umami receptor and transduction mechanism: is it a selective intestinal mucosa. Glutathione clearly plays an important taste? Umami perception-recognition and palatability: nutritional role in the protection of the mucosa from peroxide damage and from dietary toxins. These results raise the intriguing The Umami receptor is present in humans and questions whether dietary GLU is an indispensable factor for gives rise to a selective taste. The Umami receptor is specific for GLU but might also detect other free amino acids.
Considerable behavioral and electrophysiolo- Intestinal metabolism of GLU derived from natural sources or food gical evidence already existed in the 1980s supporting the additives and its function: are there differences? notion that GLU (umami) represents a fifth basic taste, Food-derived protein-bound and free GLU and separate from sweet, sour, salty and bitter or combinations of GLU derived from food additives are similarly metabolized in these tastes. For example, in human taste testing studies, subjects could differentiate umami tastes from those of theother basic tastes, in both simple and complex food matrices It is well known that GLU penetrates carrier- (Yamaguchi, 1987). In electrophysiological studies, record- mediated but largely Na( þ )-independent through the cell ing from afferent chorda tympani fibers in dogs, taste cells membranes. There are no differences in luminal uptake were found that responded to GLU application to the tongue between GLU liberated from proteins, natural free GLU and independent of sodium receptor stimulation (sodium recep- additive GLU. All GLU taken up is used for the diverse tors were blocked with amiloride) (Nakamura and Kurihara, synthesis processes in intracellular compartments (Kovacevic 1991). In addition to these earlier results, glossopharyngeal and McGivan, 1983; Hundal et al., 1986; Low et al., 1992).
afferent fibers were identified in mice that responded to GLU(and mononucleotide) applications to the tongue, but not tothe other basic tastants (Kurihara and Kashiwayanagi, 2000).
Fetal development: does the placenta barrier control GLU transfer? More recently, attempts have been made to identify the The placenta barrier controls GLU transfer even specific type of receptor on the tongue that mediates umami in situations of elevated maternal plasma levels. The taste. One approach has been pharmacologic, and it was limitation of transplacental transfer is due to placental examined in rats and humans whether agonists at known neuronal GLU receptors are perceived as having umamitaste. In rats, studies have focused on taste preference and taste synergy studies, and evidence was found for an umami Stegink et al. (1975) in pregnant females showed that even taste receptor that shares pharmacologic similarities with the very large, intravenously infused doses of GLU penetrate metabotropic GLU receptor 4-subtype (mGLU-R4) (Delay only to a minor extent into the fetal circulation. A et al., 2000). In human studies, subjects reported the biochemical explanation is offered by the recent studies in presence and intensity of umami taste for a variety of GLU sheep, in which the placenta was shown to extract GLU from receptor agonists. The result was that the umami taste both the maternal and fetal circulations for use as a principal receptor is probably a metabotropic, but not an ionotropic GLU receptor, perhaps somewhat similar to, but not Up to which maternal plasma level this may be applicable identical with the metabotropic GLU receptor subtype-4.
has been also tested in rhesus monkeys their placenta Kurihara and Kashiwayanagi (2000) concluded from their being morphologically and functionally the most similar to human studies that the umami taste receptor may be a human placenta (Stegink et al., 1975). Pregnant females received during 1 h intravenous drip containing 0.15, 0.17– A second approach has been to use molecular techniques 0.19, 0.22 or 0.40 g MSG/kg bw, respectively. Infusions with to identify candidate umami taste receptors. One strategy, based on earlier work suggesting that the mGLU-R4 might Based on broad range of experimental data and human function as an umami taste receptor, has been to search for studies, MSG or calcium diglutamate can be used cautiously the expression in taste tissue of the mGLU-R4. A gene by the consumer in order to increase palatability and can expressing an N-terminal truncated version of the mGLU-R4 also be used selectively by nutrition experts in order to has been found in rat taste buds; this receptor elaborates influence food selections towards a healthy diet composition umami taste receptor-like properties (Chaudhari et al., 2000).
specifically in individuals with either a low food intake or Another strategy has been to use novel screening strategies to create a taste-bud enriched cDNA library from rats, anduse it to search for candidate taste receptors. This approachhas led to the identification of a set of G-protein-coupled receptors, organized into two receptor families (taste recep-tor 1 (T1R) and taste receptor 2 (T2R)) that elaborate the basic taste modalities, including umami (Hoon et al., 1999; Food has to be safe. This statement is of paramount meaning Nelson et al., 2002; Zhao et al., 2003). Umami taste receptors in the legislation of virtually all countries and governs the fall into the T1R family of receptors, and recent studies in work of international bodies dealing with food and/or knockout mice suggest that a particular member of the T1R health. However, inappropriate eating habit, or individual family (the T1R1 þ 3 variant) serves as an L-amino-acid predisposition (e.g. idiosynkrasie, metabolic disorders) show receptor in rat taste buds (Zhao et al., 2003), and an that it is not possible to make food absolutely safe for umami-specific taste receptor in humans (Li et al., 2002).
every person and under all circumstances. Therefore, the Finally, a recent report has identified in humans a specific definitions of food safety take these restrictions into ageusia for GLU, suggesting that such individuals may lack an umami taste receptor (Lugaz et al., 2002).
According to the general principles of Codex alimentarius (1995) food safety is the assurance that food will not causeharm to the consumer when it is prepared and/or eaten Does GLU improve palatability and does it have nutritional according to its intended use. Several other definitions are  ISO 8402: Food safety means the state in which risk of taste. Sodium or calcium salts of GLU increases acceptability harm to persons or damage is limited to an acceptable of new flavors. Liking of GLU-enriched foods may contribute to maintain nutrient intake in subjects with reduced  ISI/CEI Guide 2: Food safety means freedom from chemosensory sensitivity, for example institutionalized  OECD, 1993: ‘A food is safe if there is a reasonable certainty that no harm will result from its consumption Taste and smell losses can reduce appetite and under the anticipated conditions of use’.
may lead to inadequate dietary intake, a situation frequently Thus, one is aware that virtually no food can be described occurring in elderly. Most of these chemosensory deficits are to which a zero-risk may apply. This background leads to the not reversible. Symptomatic treatment including intensifica- question as to the ‘acceptable level of risk’ or ‘the reasonable tion of taste and odor can compensate in part for perceptual certainty’. It is commonly accepted that this limit rests on losses. One method for treatment involves a sensory enhancement of foods with flavors and MSG. Several studies Whereas it is still a problem to assess the safety of a showed that amplification of flavor and taste can improve complex food, the assessment of a distinct compound that food palatability, increase salivary flow and local immunity may be employed as a food additive is a well established and thereby at least acceptance of food (Schiffman, 2000; procedure. The principles of which follow the recommenda- tions of FAO/WHO Expert Committees and base on testing In institutionalized elderly persons and in hospitalized all toxicological endpoints as well as the definition of diabetic patients, the addition of MSG to specific foods in a acceptable daily intake amounts that take into account a lunch meal induced an increased intake for those foods with safety margin of a factor 100. This experimentally deter- a subsequent decreased intake of foods presented later in the mined amount is defined as the ‘no observed adverse effect meal. In both populations only food selection was affected by MSG but meal size remained the same (Bellisle, 1998).
With the idea to reduce sodium intake studies have been performed to exchange sodium salts in foods with calcium Can we define a safe level of intake regarding added GLU? salts, for example calcium diglutamate. Addition of calcium Based on dietary animal studies (metabolic diglutamate raised liking of fried sausages (Bratwurst) similar control), a NOAEL of 16 000 mg/kg body weight was to the corresponding sodium salt-enriched products (Wood- calculated in weaning animals, on parenteral supply 500– There is an early literature showing that free GLU sensitivity also showed no response to MSG; 80% of this GLU can be administered chronically to humans in very group demonstrated aspiring sensitivity. The investigators large doses with no ill effect. An example of this is the study concluded that MSG does not provoke bronchospasm of Bazzano et al. (1970), in which doses up to 147 g/day GLU were given for 30 days or more, with no adverse effects In a survey of Stevenson (Stevenson, 2000) a total of 45 reported (147 g/day in a 70 kg male would be about 210 mg/ patients out of four studies cited are listed. The survey was on kg bw/day). Other studies date even earlier that is from the patients who reported asthma attacks after the consumption 1940s through the 1960s, for the most part. In animals, there of meals in oriental restaurants. None of the patients showed is the multigenerational study performed by Anantharaman reactions on orally applied GLU per se. In contrast there are in the 1970s (Anantharaman, 1979) using doses of 6000– two former studies (Allen et al., 1987; Moneret-Vautrin, 7000 mg/kg bw/day into male and female mice and genera- 1987) reporting GLU provoking a reaction – under simple tions of offspring with no ill effects whatsoever. But, no blind conditions after discontinuing the antiasthma-medica- LOAEL or NOAEL has been set for added GLU, at least by the tion – in 16 out of 62 high-risk patients. Out of a total of 109 US Committee on Dietary Reference Intakes (Panel on asthmatics tested none showed reactions on oriental food An inquiry brought only one study up in which high-dose GLU supplementation (up to 8% in the diet) improved Do we have additional knowledge on the effect of added GLU on significantly the immune status of rats recovering from lung and immune system since 1997 until now? chemotherapy. The immune-enhancing effect of dietary GLU was dose-dependent and more pronounced after a adverse effects on the lung. Other new data derived from longer duration of dietary GLU intake (Lin et al., 1999).
in vitro studies show differing results but these cannotbe transferred to the situation of GLU derived from food.
The existence of GLU-induced asthma, even in history- Can groups sensitive to GLU (derived from either natural food or positive patients, has not been established firmly.
food additives) be defined? Are there at present placebo controlled The information on the effects of high GLU concentra- studies available sufficiently to either exclude or promote side tions on immunological parameters is scarce.
No, there is no clear description of a sensitive In 1981, two experiments were described in phenotype. One multicenter study with real placebo did not which asthma attacks could be provoked by ingesting 2.5 g find any effect of GLU when MSG was given with food.
GLU (Allen and Baker, 1981). Recently, GLU receptors of the Another study did not show reproducible effects.
NMDA subtype have been identified in the lungs of rats,which might be responsible for the hypersensitivity of Regarding GLU sensitivity, two articles are asthmatics (Dickmann et al., 2004). A survey of Schwartz- relevant since 1997 (Yang et al., 1997; Geha et al., 2000).
stein (Schwartzstein, 1992) documented 19 cases of asthma Yang et al. conducted a double-blind study in self-identified, attacks induced by GLU dosages (as MSG) in the gram range.
GLU-sensitive subjects. They received placebo or 5 g MSG in Here, the design of the study has to be criticized: under liquid in random order, and those showing a response to one double-blind conditions only a single attack could be of the treatments were retested with 1.25, 2.5 and 5 g MSG.
A response was defined as any two of a list of 10 symptoms Concerning lungs in relation to asthma two studies have listed in a recent expert panel-government report (Raiten appeared since 1997. Woods (Woods et al., 1998) examined a et al., 1995) Subjects reported any symptoms, and were group of asthmatic subjects who believed that added GLU unaware of the index symptoms being followed. In the first was a cause of their asthma. They conducted a double-blind, trial, 22 of 61 subjects responded to 5 g MSG, but not placebo placebo-controlled, crossover study (n ¼ 12); subjects in- (18 responded to neither treatment, six responded to both gested placebo (lactose), 1 or 5 g MSG on separate test days, and 15 responded to placebo). When analyzed for order and lung function was followed for 12 h. They observed no effects of treatment (an assessment of subject bias), positive significant effect of MSG on lung function at either dose, responses to placebo were greater when it was administered relative to placebo. Woessner et al. recruited groups of during the first, rather than the second challenge. Subjects asthmatic patients who reported (a) sensitivity to added showing a response to one treatment only (n ¼ 37:22 GLU (n ¼ 30) and (b) no GLU sensitivity (n ¼ 70). Subjects MSG þ 15 placebo; the study was double-blind) were then received, single-blind, on separate days either placebo or retested. An analysis of total occurrences in all subjects of the 2.5 g MSG, and were followed for 12 h. All subjects were 10 index symptoms revealed that headache, muscle tight- tested for aspirin sensitivity. Subjects who reported sensiti- ness, numbness, weakness and flushing were increased when vity to GLU showed no difference in response to placebo MSG was ingested, and a dose-effect was evident.
and MSG. Twelve of these subjects demonstrated aspiring The Yang study evaluated the total occurrence of all sensitivity (a positive control). Subjects who reported no index symptoms of GLU, and did not require that subjects show reproducibility of symptoms with retesting, a key issue addition, hard clinical criteria are requested when testing of a recent US expert panel review (Raiten et al., 1995).
patients with food additives (Asero, 2004).
Another recent study addressed the issue of symptomreproducibility among subjects who identified themselves The Geha study (Geha et al., 2000) had four sequential tests, the first two being identical to those in the Yang study In cases of an impaired blood/brain barrier (BBB) GLU from (above). A total of 130 subjects entered the first phase of the blood might cross the barrier and might cause toxic effects study, in which they received, double-blind, placebo or 5 g even at physiological plasma levels.
MSG in liquid in random order on separate days, and As the gastrointestinal tract has a very high capacity for symptoms were recorded for 2 h. Fifty subjects reported two using GLU, dietary intake (free and bound GLU) has a minor or more index symptoms following MSG ingestion, and 0 impact on plasma levels. Only high concentrations (as bolus) or 1 following placebo, 19 reported two or more symptoms (e.g. 550 mmol/l) may lead to a transient increase of plasma with MSG and placebo, 17 two or more symptoms with level. Consequently food-derived GLU (including added placebo, and 0 or 1 with MSG, and 44 0–1 symptoms with GLU as food additive in normal amounts of o1 g/day) does either MSG or placebo. Phase two (the dose–response study not further increase the risk for toxic effects in cases of an using 0, 1.25, 2.5 and 5.0 g MSG) entered 86 subjects (they impairment of BBB because plasma levels do not rise.
included all subjects who had two or more responses toeither or both treatments) and completed 69. In this phase,when total symptom occurrence was analyzed, the outcome Does the BBB control the GLU transfer under normal conditions? was similar to that observed by Yang et al. (1997): more As long as BBB is intact there is no risk for GLU subjects reported index responses as MSG dose increased.
However, the responses were then analyzed for reproduci-bility across both trials. As the MSG dose in the first trial was The BBB restricts and regulates the flux of 5 g, the reproducibility of response to the 5 g dose was substrates between the circulation and the central nervous assessed over both trials. The criterion of symptom reprodu- system. To cross the barrier substances must either cross the cibility was met by only 14 of the subjects (a total of 19 lipoid cellular membranes or be transported by selected BBB responded to MSG but not placebo, but only 14 had carriers. GLU is a polar solute, thus the passive influx is reproducible symptoms to MSG). Based on the expert panel limited to o1% of that occurring at the blood vessels of report (Raiten et al., 1995) the next phase of the study, which included 12 of the 19 subjects who responded to MSG butnot placebo (only 12 agreed to participate further), involvedadministering MSG (5 g) or placebo in capsules (to prevent Are there conditions where this barrier function regarding GLU their tasting the test substance) twice, each on separate occasions. Only two of the subjects reported two or more Several common brain pathologies are known to symptoms after MSG, but not placebo. However, neither be associated with BBB disruption. There is no assured subject reported the same symptoms following each MSG research data available whether augmented plasma levels in challenge. A final phase assessed symptom occurrence this situation influence synaptic GLU concentrations.
following the ingestion of food containing MSG (or placebo)on three separate occasions. Even though no subjects There is evidence that a doubling of plasma remained that had proven MSG-sensitivity, the two that GLU, for example after infusion of GLU containing par- responded to MSG, but not placebo, were invited to enteral nutrition augments brain edema in conditions with a participate in this phase. Both subjects reported two or more lesioned BBB (Stover and Kempski, 1999). Elevated plasma symptoms in one of the three MSG trials, and the symptoms GLU may also occur during anesthesia with isoflurane were not the same as reported in previous MSG challenges.
(Stover et al., 2004; Stover and Kempski, 2005).
The study of Geha et al. demonstrates that when a group of self-identified, GLU sensitive individuals is asked to showreproducibility in symptoms, none can do so.
Do we have data that might promote a relationship or role of The conclusions of a subsequent review by the Federation added GLU in the development of neurological degenerative of American Societies for Experimental Biology (FASEB) and the Federal Drug Administration (FDA) did not discount the At present there is no scientific data available existence of a sensitive subpopulation but otherwise con- supporting the presumption of an involvement of added curred with the safety evaluation of JECFA and the SCF GLU in the development of human neurological disease.
The trend is going to exclude GLU from food additive GLU functions in the CNS as excitatoric trans- intolerance list because of uncertainty (Young, 1997). In mitter. Therefore, high intracellular GLU concentrations concurrently with low extracellular concentrations have to animals that had received a continuous infusion of GLU be maintained. This will be reached on the one hand by a water content (edema) was significantly higher than in rats fast elimination of the released GLU by surrounding without GLU infusion. A doubling of plasma GLU concen- astrocytes and on the other hand by an active transport trations was sufficient to cause this effect, and brain edema mechanism provided at the BBB which ensures that the only worsened in those animals, which had elevated plasma spinal fluid (CSF)-GLU level is kept lower than the concen- GLU concentrations. GLU increases brain water content most likely as a consequence of glial GLU uptake systems, In the brain, GLU binds to the NMDA-receptor and which eliminate extracellular GLU together with sodium controls the intra- and extracellular (synaptic) calcium ions and – osmotically obliged – water. The deterioration of levels. In times of overactivation there is a reinforced brain edema hence was a direct consequence of homeostatic calcium influx into the cell leading finally to apoptosis.
mechanisms that prevent interaction of extracellular GLU After ischemia in definite brain sections neurons will be destroyed. Out of these damaged cells GLU will be released However, several caveats should be noted: (1) The GLU and the CSF GLU level will increase. Therefore, primarily not transporters at the BBB appear to be on the abluminal infarcted brain sections will probably also be affected.
membrane, and function to transport GLU out of the brain Basal synaptic concentrations of GLU are estimated to be (O’Kane et al., 1999). These transporters presumably would in the 2–5 mmol/l range, and rise to 50–100 mmol/l following still function in situations in which BBB permeability has release (Daikhin and Yudkoff, 2000; Meldrum, 2000). Plasma increased; (2) Glial and neuronal GLU transporters (Gold- GLU concentrations are typically 50–100 mmol/l under smith, 2000; Meldrum, 2000) would also presumably remain normal conditions (Tsai and Huang, 1999; Fernstrom et al., functional under conditions of increased BBB permeability 1996) and do not rise significantly even in the presence of (except if the brain is ischemic, and thus oxygen deprived, sizable oral doses of MSG (Tsai and Huang, 1999). Plasma such as during a stroke/vascular occlusion or under condi- GLU concentrations appear to rise only when pharmacologic tions of increased intracranial pressure), and help to keep doses of MSG are administered. Hence, if the BBB were to brain ECF and basal synaptic GLU concentrations low; and become permeable (for review see Ballabh et al., 2004; (3) Dietary GLU and MSG, even at a very high dose in the Neuwelt, 2004), or BBB GLU transporters were to become daily diet (Tsai and Huang, 1999), do not raise plasma GLU compromised (they normally function to transport GLU out concentrations (MSG intake is self-limiting, since it is not of the brain (O’Kane et al., 1999), one might imagine that palatable at high concentrations in foods (Yamaguchi, synaptic GLU concentrations could rise, which would be 1987)); hence, dietary GLU or MSG should not influence sufficient to stimulate GLU receptors.
synaptic GLU concentrations, per se, if BBB permeability were Few studies to date have searched for changes in BBB GLU transport in physiologic and pathophysiologic settings.
However, a growing body of evidence addresses alterationsin BBB permeability (typically to large molecules). For Are toxicological data derived from animal experiments example, increases in BBB permeability have been reported (dose–effect-relations) directly transferable to humans? to accompany aging (Shah and Mooradian, 1997), Alzhei- Comparative functional and metabolic studies mers dementia (Skoog et al., 1998; Ujiie et al., 2003), type II in a variety of animals including primates and human diabetes (Starr et al., 2003), and hypertension (Mooradian, studies provide a rational safety evaluation for human 1988; Mayhan, 1990; Ueno et al., 2004). BBB permeability also increases with increasing plasma osmolarity (Tamakiet al., 1984), and after the administration of certain drugs Relevant literature has already been summar- (Boertje et al., 1992). Presumably, increases in BBB perme- ized and listed (Biesalski et al., 1997; Walker and Lupien, ability would permit increased entry of all molecules from 2000). Briefly, the toxicologic database available for review the plasma, including molecules such as GLU. However, includes acute, subchronic and chronic toxicity studies as most studies that have specifically examined GLU transport well as studies on reproductive toxicity and teratology in (penetration) into the brain, deal with aging, in which GLU rats, mice and dogs. GLU has a very low acute toxicity under transport appears to be not different in adult and aged normal circumstances; the oral dose that is lethal to 50% of animals (Shah and Mooradian, 1997), and with hyperten- subjects (LD50) in rats and mice is 15000–18000 mg/kg bw, sion, in which GLU uptake into brain may be increased (Tang respectively. Subchronic and chronic toxicity studies of up to et al., 1993; Al-Sarraf and Philip, 2003).
2 years duration in mice and rats, including a reproductive However, there is evidence that a doubling of plasma GLU, phase, did not reveal any specific adverse effects at dietary e.g. after infusion of GLU-containing parenteral nutrition levels of up to 4%. Reproduction and teratology studies using augments brain edema in conditions with a lesioned blood the oral route of administration have been uneventful brain barrier (Kempski et al., 1990). In those experiments the indicating that the fetus and suckling neonate was not BBB of rats was focally destroyed by a freezing lesion, and exposed to toxic GLU levels from the maternal diet through water content of the brain was measured a day later. In transplacental transfer. Based on these results from mammals authoritative organizations have affirmed the safety of added amino acids accounting for around 50% of total free amino GLU at levels normally consumed by the general population.
acids (Agostoni et al., 2000; Ramirez et al., 2001). Actualanalyses of free GLU in milk samples of mothers delivered ontime revealed 8277342 mmol/l for transitional milk and Large doses of dietary GLU: do they have an impact on endocrine 8687462 mmol/l for mature milk (Meinardus et al., 2004; Jochum et al., 2006). Considering a daily feeding of 600 ml, a Very high doses of GLU influence the insulin 4-kg-infant would ingest around 130 mmol/kg (19 mg/kg) free reaction induced by an unphysiologically high glucose load.
GLU. Moreover, the intake of bound GLU would reach ca.
1.3–1.5 g/day depending of the protein content of the milk.
Recently, Chevassus et al. (2002) gave 10 g MSG The role of free amino acids in breast milk is still under or placebo in capsules orally to fasted human subjects at the debate. It is, however, speculated that especially free GLU time they received a 75 g glucose load, and followed the and glutamine might have a double role of protecting the plasma insulin changes over time. There was a significant intestinal growth while supplying functional substrates to positive correlation between plasma insulin area-under-the- the nervous tissue (Agostoni et al., 2000; Jochum et al., curve and peak plasma GLU concentrations, suggesting to 2006). Consequently, the intake of free GLU in suckling the authors that GLU enhanced glucose-induced insulin babies is seen as a useful physiological support of growth and secretion, consistent with the existence of stimulatory GLU metabolic development. In addition, GLU is seen as a rapidly receptors on pancreatic beta cells (Hinoi et al., 2004). In this available nitrogen donor in growing mammals due to its study, peak plasma GLU concentrations were about doubled central role in transamination processes.
over baseline and placebo values. Studies of similar designhave also been conducted by Graham and associates, butadministering MSG (or a placebo) by itself to fasting subjects; with this design, significant increases in plasma insulinconcentrations are clearly evident (Graham et al., 2000; Agostoni C, Carratu` B, Boniglia C, Riva E, Sanzini E (2000). Free amino acid content in standard infant formulas: comparison withhuman milk. J Am Coll Nutr 19, 434–438.
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