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Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults
Abstract
Aspartame (APM) is a widely used dipeptide sweetener (L-aspartyl-L-phenylalanine methyl ester). It has been suggested that excessive use of APM might elevate plasma aspartate, phenylalanine, and/or methanol concentrations to levels that are potentially harmful. Six normal young adults ingested eight successive servings of unsweetened and APM-sweetened beverage at one-hour intervals in a balanced crossover design. In one part, the beverage was not sweetened. In the other, each serving of beverage provided 600 mg APM, a dose equivalent to the amount provided by 36 oz of APM-sweetened diet beverage. Plasma aspartate concentration was not significantly increased after ingestion of unsweetened or APM-sweetened beverage. Similarly, ingestion of the unsweetened beverage had no significant effect on plasma phenylalanine concentration. However, ingestion of APM-sweetened beverage significantly increased plasma phenylalanine levels 1.41 to 2.35 mumol/dL above baseline 30 minutes after ingestion. Plasma phenylalanine values reached a steady state after administration of four to five servings and did not exceed normal postprandial values at any time. Blood methanol and formate concentrations remained within normal limits. The data indicate ready metabolism of APM when administered at levels that may be ingested by normal individuals who are heavy users of diet beverages.
... Methanol is highly toxic and can be absorbed through any route of exposure [3,7]. It quickly spreads throughout the body and accumulates in different tissues because of body fluids' motion [4,7]. ...
... Methanol is highly toxic and can be absorbed through any route of exposure [3,7]. It quickly spreads throughout the body and accumulates in different tissues because of body fluids' motion [4,7]. Around 10% of the byproduct is converted into formate, which is either excreted or further metabolized into formaldehyde and other toxic derivatives that can severely damage the brain and liver [4,7,8]. ...
... It quickly spreads throughout the body and accumulates in different tissues because of body fluids' motion [4,7]. Around 10% of the byproduct is converted into formate, which is either excreted or further metabolized into formaldehyde and other toxic derivatives that can severely damage the brain and liver [4,7,8]. Consumption of aspartame during conception could lead to birth defects due to the high concentrations of phenylalanine in the placenta, which can cause mental retardation and indicate the toxicity of aspartame metabolites [8]. ...
Aspartame, a widely used artificial sweetener, is present in many food products and beverages worldwide. It has been linked to potential neurotoxicity and developmental defects. However, its teratogenic effect on embryonic development and the underlying potential mechanisms need to be elucidated. We investigated the concentration- and time-dependent effects of aspartame on zebrafish development and teratogenicity. We focused on the role of sirtuin 1 (SIRT1) and Forkhead-box transcription factor (FOXO), two proteins that play key roles in neurodevelopment. It was found that aspartame exposure reduced the formation of larvae and the development of cartilage in zebrafish. It also delayed post-fertilization development by altering the head length and locomotor behavior of zebrafish. RNA-sequencing-based DEG analysis showed that SIRT1 and FOXO3a are involved in neurodevelopment. In silico and in vitro analyses showed that aspartame could target and reduce the expression of SIRT1 and FOXO3a proteins in neuron cells. Additionally, aspartame triggered the reduction of autophagy flux by inhibiting the nuclear translocation of SIRT1 in neuronal cells. The findings suggest that aspartame can cause developmental defects and teratogenicity in zebrafish embryos and reduce autophagy by impairing the SIRT1/FOXO3a axis in neuron cells.
... In the second study, 600 mg of aspartame was administered every hour for 8 h (Stegink et al., 1989a), which approximates the amount of aspartame in about 10 liters of beverage sweetened with 100% aspartame given over 8 h. Aspartame had no significant effect on plasma aspartate concentrations. ...
... Hence, the metabolism of methanol to formate and the renal clearance of There is no accumulation of phenylalanine with repeated aspartame dosing. Adapted from Stegink et al. (1989a) formate were sufficient to prevent methanol or formate accumulation in the body even after this large dose of aspartame (Stegink et al., 1989a). ...
... Hence, the metabolism of methanol to formate and the renal clearance of There is no accumulation of phenylalanine with repeated aspartame dosing. Adapted from Stegink et al. (1989a) formate were sufficient to prevent methanol or formate accumulation in the body even after this large dose of aspartame (Stegink et al., 1989a). ...
... In the second study, 600 mg of aspartame was administered every hour for 8 h (Stegink et al., 1989a), which approximates the amount of aspartame in about 10 liters of beverage sweetened with 100% aspartame given over 8 h. Aspartame had no significant effect on plasma aspartate concentrations. ...
... There is no accumulation of phenylalanine with repeated aspartame dosing. Adapted from Stegink et al. (1989a) formate were sufficient to prevent methanol or formate accumulation in the body even after this large dose of aspartame (Stegink et al., 1989a). ...
... There is no accumulation of phenylalanine with repeated aspartame dosing. Adapted from Stegink et al. (1989a) formate were sufficient to prevent methanol or formate accumulation in the body even after this large dose of aspartame (Stegink et al., 1989a). ...
Over 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using much greater doses than people could possibly consume. Its safety was further confirmed through studies in several human subpopulations, including healthy infants, children, adolescents, and adults; obese individuals; diabetics; lactating women; and individuals heterozygous (PKUH) for the genetic disease phenylketonuria (PKU) who have a decreased ability to metabolize the essential amino acid, phenylalanine. Several scientific issues continued to be raised after approval, largely as a concern for theoretical toxicity from its metabolic components--the amino acids, aspartate and phenylalanine, and methanol--even though dietary exposure to these components is much greater than from aspartame. Nonetheless, additional research, including evaluations of possible associations between aspartame and headaches, seizures, behavior, cognition, and mood as well as allergic-type reactions and use by potentially sensitive subpopulations, has continued after approval. These findings are reviewed here. The safety testing of aspartame has gone well beyond that required to evaluate the safety of a food additive. When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.
... One of the largest studies commissioned by the aspartame manufactures are of the opinion that: 'in most cases aspartate concentrations were not significantly affected by aspartame ingestion' (Stegink et al., 1988; Stegink et al., 1989). If read in another way, it suggests that in some cases aspartic acid was, indeed, increased. ...
... Aspartic acid is thought to play a role as an excitatory neurotransmitter in the central nervous system (Watkins, 1984; Stone and Burton, 1988). Glutamate, asparagines and glutamine are formed from their precursor, aspartic acid (Stegink et al., 1989). Aspartate is inactivated by reabsorption into the presynaptic membrane and it opens an ion channel (Olney, 1975). ...
... The accumulation of formate ratherFigure 5 Production pathway of glutamate and g-aminobutyric acid (GABA) in neuronal and glial cells. Effects of aspartame on the brain P Humphries et al than methanol is itself considered to cause methanol toxicity (Stegink et al., 1989), but research has shown that formaldehyde adducts accumulate in the tissues, in both proteins and nucleic acids, after aspartame ingestion (Trocho et al., 1998). The formed adducts of the metabolic poisons alter both mitochondrial DNA and nucleic DNA. ...
The use of the artificial sweetener, aspartame, has long been contemplated and studied by various researchers, and people are concerned about its negative effects. Aspartame is composed of phenylalanine (50%), aspartic acid (40%) and methanol (10%). Phenylalanine plays an important role in neurotransmitter regulation, whereas aspartic acid is also thought to play a role as an excitatory neurotransmitter in the central nervous system. Glutamate, asparagines and glutamine are formed from their precursor, aspartic acid. Methanol, which forms 10% of the broken down product, is converted in the body to formate, which can either be excreted or can give rise to formaldehyde, diketopiperazine (a carcinogen) and a number of other highly toxic derivatives. Previously, it has been reported that consumption of aspartame could cause neurological and behavioural disturbances in sensitive individuals. Headaches, insomnia and seizures are also some of the neurological effects that have been encountered, and these may be accredited to changes in regional brain concentrations of catecholamines, which include norepinephrine, epinephrine and dopamine. The aim of this study was to discuss the direct and indirect cellular effects of aspartame on the brain, and we propose that excessive aspartame ingestion might be involved in the pathogenesis of certain mental disorders (DSM-IV-TR 2000) and also in compromised learning and emotional functioning.
... Aspartate, a metabolite of aspartame is an excitatory neurotransmitter in the central nervous system (Stone and Burton, 1988). Aspartate is also a precursor of glutamate, asparagines and glutamine (Stegink et al., 1989) and has been reported to act as a glutamate agonist at the NMDA receptor (Fountain et al., 1988). ...
... In this study, brain aspartate values (measured by spectrophotometric methods) increased with administration of aspartame, although the difference was not statistically significant. While a number of studies have reported significant increases in aspartic acid levels with administration of aspartame (Moller, 1991;Burns et al., 1991;Rajasekar et al., 2004); there are also reports of no effects (Stegink et al., 1989). However, studies have shown that even slight increases in aspartate levels in the brain can lead to excitotoxicity in the neurons due to: (i) aspartate's ability to open cationic channels leading to uncontrollable calcium (and to a lesser extent sodium) influx, triggering a cascade of intracellular enzymecontrolled reactions culminating in cell death (ii) excitotoxicity of glutamate and aspartate are major contributors to pathological cell death within the nervous system and this appears to be mediated by reactive oxygen species (superoxide dismutase levels was elevated in this study). ...
Objective
The study evaluated changes in open field behaviours, cerebral cortical histomorphology and biochemical markers of oxidative stress following repeated administration of aspartame in mice.
Methodology
Adult mice were assigned into five groups of twelve each. Vehicle (distilled water), or aspartame (20, 40, 80 and 160 mg/kg body weight) were administered orally for 28 days. Horizontal locomotion, rearing and grooming were assessed after the first and last dose of aspartame. Sections of the cerebral cortex were processed and stained for general histology, and also examined for neuritic plaques using the Bielschwosky’s protocol. Glial fibrillary acidic protein (GFAP) and neuron specific enolase (NSE) immunoreactivity were assessed using appropriate antibodies. Aspartate and antioxidant levels were also assayed from cerebral cortex homogenates. Data obtained were analysed using descriptive and inferential statistics.
Results
Body weight and food consumption decreased significantly with aspartame consumption. Locomotion, rearing and grooming increased significantly after first dose, and with repeated administration of aspartame. Histological changes consistent with neuronal damage were seen at 40, 80 and 160 mg/kg. Neuritic plaque formation was not evident; while GFAP-reactive astrocytes and NSE-reactive neurons increased at 40 and 80 mg/kg but decreased at 160 mg/kg. Superoxide dismutase and nitric oxide increased with increasing doses of aspartame, while aspartate levels showed no significant difference.
Conclusion
The study showed morphological alterations consistent with neuronal injury and biochemical changes of oxidative stress. These data therefore supports the need for caution in the indiscriminate use of aspartame as a non-nutritive sweetener.
... Glutamate and aspartate are the most common exicitotoxins known, excitoxins have a devastating effect on formation of the brain and as increased levels of which could change the basic activity level of the brain to an unhealthy state (Soffritti et al., 2006); Nosti-Palacios et al., 2014). In this study, brain aspartate values were measured by spectrophotometric methods after 28 days of aspartame, result showed that increments in brain aspartic acid was not significantly higher than seen with administration of vehicle, this corroborates studies by Stegink and his colleagues reported that: in most cases aspartate concentrations did not increase significantly with ingestion of aspartame (Stegink et al., 1989), however in some other studies administration of aspartame resulted in increased levels of brain aspartic acid (Moller, 1991;Burns et al., 1991;Rajasekar et al., 2004). Aspartic acid is believed to play an active role as an excitatory neurotransmitter in the central nervous system (Stone and Burton, 1988) it is also a precursor of brain glutamate, (Stegink et al., 1989) which in its self is an excitatory neurotransmitter. ...
... In this study, brain aspartate values were measured by spectrophotometric methods after 28 days of aspartame, result showed that increments in brain aspartic acid was not significantly higher than seen with administration of vehicle, this corroborates studies by Stegink and his colleagues reported that: in most cases aspartate concentrations did not increase significantly with ingestion of aspartame (Stegink et al., 1989), however in some other studies administration of aspartame resulted in increased levels of brain aspartic acid (Moller, 1991;Burns et al., 1991;Rajasekar et al., 2004). Aspartic acid is believed to play an active role as an excitatory neurotransmitter in the central nervous system (Stone and Burton, 1988) it is also a precursor of brain glutamate, (Stegink et al., 1989) which in its self is an excitatory neurotransmitter. Aspartate is thought to have an increased likelihood for depolarization of the postsynaptic membrane; even short-lived increases of aspartate are enough to induce neuroendocrine disturbances. ...
This study investigated the histomorphological, immunohistochemical and neurobehavioural effects of aspartame in mice. This was with a view to ascertaining the effects of aspartame on brain histomorphology, neuritic plaque formation, neurogenic markers, and neurobehavioural indices such as central excitation or inhibition, anxiety and memory.
Sixty male Swiss mice weighing 20-22 g were assigned into 5 groups (A-E) of twelve mice each. Group A received vehicle (distilled water) at 10 ml/kg, while groups B to E received aspartame at 20, 40, 80 and 160 mg/kg body weight, daily for 28 days via an oral cannula. Food and water intake were measured daily, while body weight was measured weekly. The Open field was used to measure locomotion, rearing and grooming, Y-maze for spatial memory, and Elevated Plus Maze (EPM) for anxiety. Tests were conducted after the first and last doses of aspartame. At the end of the experimental period, mice were sacrificed by cervical dislocation, and their brains excised and fixed in 10% neutral buffered formalin. Sections of the cerebrum, hippocampus and cerebellum were processed, and stained using hematoxylin and eosin for general histology, cresyl violet for Nissl substance, and Bielschwolsky’s protocol for neuritic plaques. Glial fibrillary acidic protein (GFAP) and neuron specific enolase (NSE) immunoreactivity were assessed using appropriate antibodies. Stained sections were examined under a microscope, and captured images analysed using Image J software. Data were subjected to analysis of variance (ANOVA) followed by Tukey HSD tests, p <0.05 was taken as accepted level of significance.
Results showed that food consumption decreased significantly (F=3.09, p=0.001) in groups B-E(25.82±0.53, 26.15±0.37, 24.97±1.25, 24.17±1.83 g respectively) compared to A(27.33±0.33 g), body weight decreased significantly (F=3.58, p=0.001) in groups B-E(28.3±2.3, 21.36±4.4, 20.3±2.2, 17.5±2.2 g respectively) compared to A(31.19±4.1 g). Horizontal locomotion increased significantly (F=21.2, p=0.011) in groups B-E(148.5±12.2, 214.3±6.2,156±4.1, 182.2±5.4 respectively) compared to A(93.5±8.1), rearing increased significantly (F=8.18, p=0.001) in groups B-E(88.5±8.4, 84.3±5.2, 58.3±3.6, 65±2.9 respectively) compared to A(35.3±2.4), while grooming increased significantly (F(=21.2, p=0.001) in groups B-E(28.2±2.1, 15.83±1.8, 13.67±2.2, 30±1.8 respectively) compared to A(2.7±0.8). In the EPM, there was a significant (F=16.8, p=0.001) decrease in percentage time spent in open arms following acute, and subchronic doses of aspartame in groups B-E(11.1±0.9, 14.78±1.6; 18.3±2.7, 24.2±1.6; 11±1.7, 16.7±2.3; 2.1±2.3, 2.6±2.1% respectively) compared to A(24.6±0.8, 19.4±0.3%). In the Y-maze, memory increased significantly (F=3.56, p=0.001) in groups B(79.22±1.4%) and decreased in E(50.67±1.1%) compared to A(62.2±0.9%) with subchronic doses and showed no significant difference with acute doses. Brain weight increased significantly (F =33.16, p=0.001) in groups C-E(0.0068±0.01), 0.0096±0.004, 0.0097±0.004 g/m2 respectively) compared to A(0.0056±0.01 g/m2). In the cerebral cortex, pyramidal cell density deceased significantly (F=45.12, p=0.012) in groups C-E(114.83 ± 0.17, 102.83 ± 0.17, 88.50 ± 0.34 cells/µm respectively) compared to A(158.00±0.26 cells/µm), and astrocyte density increased significantly in C-E (101.67±0.2, 73.02±0.40, 72.83±0.40 cells/µm respectively) compared to A(44.67 ± 0.21 cells/µm). In the hippocampus, pyramidal cell density decreased significantly (F=12.6, p=0.001) in groups C-E(19.50±0.22, 9.74±0.24, 8.21±0.21 cells/µm respectively) compared to A(25.17±0.31 cells/µm), while astrocyte density increased significantly in groups C-E(122.8±0.11, 11.8±0.41, 117.3±0.33 cells/µm respectively) compared to A(58.00±0.27 cells/µm). Purkinje cell density in the cerebellum decreased significantly (F=40.33, p=0.021) in groups C-E(40.29 ± 0.18, 37.29 ± 0.18, 22.14 ± 0.26 cells/µm respectively) compared to A(50.48 ± 0.20 cells/µm), while astrocyte density increased significantly in groups B-E(39.86 ± 0.26, 51.14 ± 0.26, 48.41 ± 0.34, 47.29 ± 0.36 cells/µm respectively) compared to A(20.86 ± 0.25 cells/µm). Disorganization of Nissl substance and presence of deeply stained neurons were also evident in groups C, D and E in the cerebral cortex, hippocampus and cerebellar cortex. Neuritic plaques formation with Bielschowsky staining was not evident in any of the groups, while GFAP positive astrocytes and NSE positive neurons increased in groups C. D and E in the cerebral cortex, hippocampus and cerebellar cortex.
The study concluded that aspartame in acute and subchronic doses resulted in central excitation, anxiety and neuronal injury in the cerebral cortex, hippocampus and cerebellar cortex in mice; suggesting a need for caution in its use as a non-nutritive sweetener.
... 24,66 Aspartic acid, the precursor of asparagine synthesis, regulates the immune system by protecting intestinal integrity from LPS inflammation. [67][68][69] Alanine and glutamine prevent the accumulation of nitrogen (ammonia) in muscle to alleviate fatigue. [70][71][72] Moreover, serine, threonine, and methionine have been demonstrated to be immuneomodulatory, especially in ameliorating the intestinal structure, attenuating inflammation, and boosting the abundance of beneficial bacteria (Lachnospiraceae and Lactobacillus). ...
... The rates of intestinal absorption of β-Asp-Phe and aspartame diketopiperazine are small [76]. The group of Lewis Stegink was particularly active and performed a number of clinical studies on adults, children, and infants, involving acute (single-dose or repeated doses over less than 1 day) or prolonged (e.g., daily for 13 consecutive weeks) intake of aspartame doses, sometimes higher than the ADI (up to 200 mg/kg body weight) (Table A1) to assess the pharmacokinetics and demonstrate the lack of toxicity of aspartame decomposition products [9][10][11][12][13][14][15][16]81], except for subjects with genetic traits resulting in low plasma α-Asp-Phe hydrolase activity [17]. However, other clinical studies reached different conclusions, showing adverse effects of aspartame, particularly in subjects with neurological or psychiatric conditions, such as migraines [82,83], other headaches [84,85], or unipolar depression [18]. ...
Aspartame is the methyl-ester of the aspartate-phenylalanine dipeptide. Over time, it has become a very popular artificial sweetener. However, since its approval by the main food safety agencies, several concerns have been raised related to neuropsychiatric effects and neurotoxicity due to its ability to activate glutamate receptors, as well as carcinogenic risks due to the increased production of reactive oxygen species. Within this review, we critically evaluate reports concerning the safety of aspartame. Some studies evidenced subtle mood and behavioral changes upon daily high-dose intake below the admitted limit. Epidemiology studies also evidenced associations between daily aspartame intake and a higher predisposition for malignant diseases, like non-Hodgkin lymphomas and multiple myelomas, particularly in males, but an association by chance still could not be excluded. While the debate over the carcinogenic risk of aspartame is ongoing, it is clear that its use may pose some dangers in peculiar cases, such as patients with seizures or other neurological diseases; it should be totally forbidden for patients with phenylketonuria, and reduced doses or complete avoidance are advisable during pregnancy. It would be also highly desirable for every product containing aspartame to clearly indicate on the label the exact amount of the substance and some risk warnings.
... The group of Lewis Stegink was particularly active and performed a number of clinical studies on adults, children and infants involving acute (single-dose or repeated doses over less than 1 day) or prolonged (e.g. daily for 13 consecutive weeks) intake of aspartame doses sometimes higher than the ADI (up to 200 mg/kg body weight) (Table A1) to assess the pharmacokinetics and demonstrate lack of toxicity of aspartame decomposition products [30][31][32][33][34][35][36][37][38], except for subjects with genetic traits resulting in low plasma α-Asp-Phe hydrolase activity [39]. However, other clinical studies reached different conclusions, showing adverse effects of aspartame, particularly in subjects with neurological or psychiatric conditions, such as migraine [40,41], other headaches [42,43], or unipolar depression [44]. ...
Aspartame is the methyl-ester of the aspartate-phenylalanine dipeptide. Over time it became a very popular artificial sweetener. However, since its approval by the main food safety agencies, several concerns have been raised related to neuropsychiatric effects and neurotoxicity, due to its ability to activate glutamate receptors, as well as carcinogenic risks by increased production of reactive oxygen species. Within this review we critically evaluated reports concerning the safety of aspartame. Some studies evidenced subtle mood and behavioral changes upon daily high-dose intake below the admitted limit. Epidemiology studies also evidenced associations between daily aspartame intake and higher predisposition for malignant diseases like non-Hodgkin lymphomas and multiple myelomas, particularly in males, but association by chance still could not be excluded. While the debate over the carcinogenic risk of aspartame is ongoing, it is clear that its use may pose some dangers in peculiar cases, such as patients with seizures or other neurological diseases; it should be totally forbidden for patients with phenylketonuria, and reduced doses or complete avoidance are advisable during pregnancy. It would be also highly desirable for every product containing aspartame to clearly indicate on the label the exact amount of the substance and some risk warnings.
... Aspartame consists of two amino acids; L-phenylalanine and L-aspartic acid are esterified into methyl alcohol and generate about phenylalanine (50%), aspartic acid (40%), and methyl alcohol (10%) by weight after being metabolized in the body [1]. The levels of its metabolites are increased in the blood following aspartame's intake [2]. The body uses these components in the same way as natural foods such as milk, fruit, and vegetables [3]. ...
Background: For type II diabetes (T2D) subjects to better regulate carbohydrate consumption and manage blood glucose levels, a non-nutritive sweetener (aspartame) is prescribed as an alternative to natural sugar. Previous studies show that there was a 68% rise in the probability of aspartame consumers developing T2D compared with non-consumers. In diabetes and inflammation, deformed red blood cells (RBCs) and atypical fibrin fibre formation or an altered fibrin structure are especially prevalent. Objective: The aim of this study was to investigate, in subjects with T2D taking aspartame, clot viscoelasticity and platelet structure. Methodology: Blood was drawn from 12 T2D subjects from the diabetic clinic at the Steve Biko Academic Hospital, South Africa. Blood was used to perform a full blood count, thromboelastography (TEG) and scanning electron microscopy (SEM). Results: SEM showed increased platelet activation and abnormal TEG parameters in T2D consuming aspartame. Conclusion: A hypercoagulable state can increase the risk of thromboembolic complications and an increased incidence of vascular disease. This knowledge may be used to build awareness among consumers of aspartame.
... Blood analyses were carried out in six subjects who ingested aspartame at 200 mg kg −1 but, no significant increases in blood formate concentration were noted [12]. In a subsequent 1989 study in which six adults ingested four servings of beverage each containing 600 mg of aspartame over several hours, equivalent to a typical ADI, blood methanol and formate concentrations remained below the limit of detection of the techniques used [13]. ...
Aspartame, methyl-L-α-aspartyl-L-phenylalaninate, is used worldwide as a sweetener in foods and drinks and is considered to be safe at an acceptable daily intake (ADI) of 40 mg per kg of body weight. This compound is completely hydrolyzed in the gastrointestinal tract to aspartic acid, phenylalanine and methanol, each being toxic at high levels. The objective of the present study was to quantify the volatile methanol component in the exhaled breath of ten healthy volunteers following the ingestion of a single ADI dose of aspartame. Direct on-line measurements of methanol concentration were made in the mouth and nose breath exhalations using selected ion flow tube mass spectrometry, SIFT-MS, several times before aspartame ingestion in order to establish individual pre-dose (baseline) levels and then during two hours post-ingestion to track their initial increase and subsequent decrease. The results show that breath methanol concentrations increased in all volunteers by 1082 ± 205 parts-per-billion by volume (ppbv) from their pre-ingestion values, which ranged from 193 to 436 ppbv to peak values ranging from 981-1622 ppbv, from which they slowly decreased. These observations agree quantitatively with a predicted increase of 1030 ppbv estimated using a one-compartment model of uniform dilution of the methanol generated from a known amount of aspartame throughout the total body water (including blood). In summary, an ADI dose of aspartame leads to a 3-6 fold increase of blood methanol concentration above the individual baseline values.
... For children and adults with diabetes, the daily consumption of aspartame in the worst-case scenario also did not exceed the ADI (298). When volunteers consumed 600 mg aspartame eight times a day at 1-h intervals, there were no detectable differences in their blood methanol levels (434). It is worth mentioning that the average body weight of the volunteers was 70.8 Ϯ 13.5 kg; thus the doses of aspartame used in the experiment exceeded the present ADI. ...
... In this present study (40 mg/kg) for 90 days aspartame exposure we aim to evaluate the formate level and our finding shows an increased formate level in aspartame treated animals which may be an indicative for oxidative damage caused by aspartame metabolites [68e70]. The accumulation of formate rather than methanol is itself considered to cause methanol toxicity [47]. It is relevant to point out that in the earlier report on aspartame there was marked increase in the corticosteroid level in the plasma for (75 mg/kg) [14] which indicate that the dietary sweetener aspartame could act as a chemical stressor. ...
Though several studies on toxic effect of aspartame metabolite have been studied, there are scanty data on whether aspartame exposure administration could release formate, a methanol metabolite thereby inducing oxidative stress and neurodegeneration in brain discrete region. To mimic the human methanol metabolism, the methotrexate (MTX) treated folate deficient rats were used. Aspartame was administered orally to the MTX treated animals and was studied along with controls and MTX treated controls. Oral intubations of FDA approved 40 mg/kg b.wt aspartame were given daily for 90 days. The locoemotor activity and emotionality behavior in the aspartame treated animals showed a marked increase in the immobilization, fecal bolus with a marked decrease in ambulation, rearing, grooming. The anxiety behavior in the aspartame treated animals showed a marked decrease in percentage of open arm entry, percentage of time spent in open arm and number of head dips. It is appropriate to point out, formal-dehyde and formate could have led to an increased formation of free radical in the aspartame treated animals resulting in altered neurobehavioral changes owing to neuronal oxidative damage. Aspartame induced ROS may be also linked to increased neuronal apoptosis. In this study the aspartame treated animals showed an up regulation in the apoptotic gene expression along with protein expression in the respective brain region indicating the enhancement of neuronal cell death. This study intends to corroborate that chronic aspartame consumption can alter the behavior and neurodegeneration in brain discrete regions.
... Elevated levels of methanol have been reported following consumption of alcohol or large quantities of fruit (Lindinger et al., 1997). It is a product of the degradation of pectin by colonic bacteria (Siragusa et al., 1988), and of metabolism of the sweetener aspartame (Stegink et al., 1989). However, and in agreement with Morisco et al. (2013) we find that fruit consumption cannot explain the increased methanol concentrations in the breath of liver patients compared to controls. ...
Background: The burden of liver disease in the UK has risen dramatically and there is a need for improved diagnostics.
Aims: To determine which breath volatiles are associated with the cirrhotic liver and hence diagnostically useful.
Methods: A two-stage biomarker discovery procedure was used. Alveolar breath samples of 31 patients with cirrhosis and 30 healthy controls were mass spectrometrically analysed and compared (stage 1). 12 of these patients had their breath analysed after liver transplant (stage 2). Five patients were followed longitudinally as in-patients in the post-transplant period.
Results: Seven volatiles were elevated in the breath of patients versus controls. Of these, five showed statistically significant decrease post-transplant: limonene, methanol, 2-pentanone, 2-butanone and carbon disulfide. On an individual basis limonene has the best diagnostic capability (the area under a receiver operating characteristic curve (AUROC) is 0.91), but this is improved by combining methanol, 2-pentanone and limonene (AUROC curve 0.95). Following transplant, limonene shows wash-out characteristics.
Conclusions: Limonene, methanol and 2-pentanone are breath markers for a cirrhotic liver. This study raises the potential to investigate these volatiles as markers for early-stage liver disease. By monitoring the wash-out of limonene following transplant, graft liver function can be non-invasively assessed.
... Both methanol and formate are endogenous chemicals with body burdens arising from dietary sources and metabolic processes. Methanol is available in the diet from the ingestion of fruits, fruit juices, alcoholic beverages, and certain vegetables, as well as from the gastrointestinal hydrolysis of the artificial sweetener, aspartame (10% methanol by weight; Stegink et al., 1989). Methanol is generated metabolically by the action of a methyltransferase system, although other enzymatic pathways likely contribute to endogenous levels. ...
A physiologically based pharmacokinetic (PBPK) model was developed for the monkey, to account for fractional systemic uptake of inhaled methanol vapors in the lung. Fractional uptake of inhaled [ 14 C]-methanol was estimated using unreported exhaled breath time course measurements of [ 14 C]-methanol from the D. C. Dorman et al. (1994, Toxicol Appl Pharmacol. 128, 229-238) lung-only exposure study. The cumulative amount of [ 14 C]-methanol exhaled was linear with respect to exposure duration (0.5 to 2 h) and concentration (10 to 900 ppm). The model estimated that forty to eighty-one percent of the of inhaled [ 14 C]-methanol delivered to the lung was taken into systemic circulation in female Cynomolgus monkeys exposed for two h to 10-900 ppm of [ 14 C]-methanol. There was no apparent trend between the percent of inhaled [ 14 C]-methanol absorbed systemically and the [ 14 C]-methanol exposure concentration. Model simulations were conducted using a single saturable Michaelis-Menten equation with Vmaxc, the metabolic capacity set to 15.54 mg/kg/h and Km, the affinity constant, to 0.66 mg/l. The [ 14 C]-methanol blood concentrations were variable across [ 14 C]-methanol exposure groups and the PBPK model tended to over-predict systemic clearance of [ 14 C]-methanol. Accounting for fractional uptake of inhaled polar solvents is an important consideration for risk assessment of inhaled polar solvents.
... For children and adults with diabetes, the daily consumption of aspartame in the worst-case scenario also did not exceed the ADI (298). When volunteers consumed 600 mg aspartame eight times a day at 1-h intervals, there were no detectable differences in their blood methanol levels (434). It is worth mentioning that the average body weight of the volunteers was 70.8 Ϯ 13.5 kg; thus the doses of aspartame used in the experiment exceeded the present ADI. ...
Methanol has been historically considered an exogenous product that leads only to pathological changes in the human body when consumed. However, in normal, healthy individuals, methanol and its short-lived oxidized product, formaldehyde, are naturally occurring compounds whose functions and origins have received limited attention. There are several sources of human physiological methanol. Fruits, vegetables, and alcoholic beverages are likely the main sources of exogenous methanol in the healthy human body. Metabolic methanol may occur as a result of fermentation by gut bacteria and metabolic processes involving S-adenosyl methionine. Regardless of its source, low levels of methanol in the body are maintained by physiological and metabolic clearance mechanisms. Although human blood contains small amounts of methanol and formaldehyde, the content of these molecules increases sharply after receiving even methanol-free ethanol, indicating an endogenous source of the metabolic methanol present at low levels in the blood regulated by a cluster of genes. Recent studies of the pathogenesis of neurological disorders indicate metabolic formaldehyde as a putative causative agent. The detection of increased formaldehyde content in the blood of both neurological patients and the elderly indicates the important role of genetic and biochemical mechanisms of maintaining low levels of methanol and formaldehyde.
Copyright © 2015 the American Physiological Society.
... A similar adverse neurologic effect of aspartate, which is produced during breakdown of aspartame [37], to glutamate has been studied. Because both glutamate and aspartate play a role as excitatory neurotransmitters in the central nervous system [38] and could cause AEs such as dizziness and headache, this is considered a limitation of this study. However, because of the high amount of glutamate given to the intervention group, we do not consider that the equal amount of aspartame given to both groups would be adequate to cause a blunting of the potential effect being studied. ...
Objective:
The aim of this study was to determine the relationship of high daily monosodium glutamate (MSG) consumption with glutamate concentrations in jaw muscle, saliva, and serum, and muscle pain sensitivity in healthy participants.
Methods:
A randomized, double-blinded, placebo-controlled study was conducted to investigate the effect of repetitive consumption of high-dose MSG on glutamate concentration in the masseter muscles measured by microdialysis and muscle pain sensitivity. In five contiguous experimental daily sessions, 32 healthy participants drank MSG (150 mg/kg) or NaCl (24 mg/kg) diluted with a 400 mL soda. The concentrations of glutamate before and after the ingestion were assessed in dialysate and plasma samples on the first and last days. Saliva glutamate concentration was assessed every day. Pressure pain threshold, pressure pain tolerance, autonomic parameters (heart rate, systolic and diastolic blood pressures) and reported side effects also were assessed.
Results:
No significant change was noted in the baseline concentration of glutamate in the masseter muscle, blood, or saliva, but the peak concentration in the masseter muscle increased significantly between day 1 and 5. A statistically significant increase in systolic and diastolic blood pressures after MSG administration was observed, as well as a significantly higher frequency of reports of nausea and headache in the MSG group. No robust effect of MSG on muscle sensitivity was found.
Conclusion:
Interstitial glutamate concentration in the masseter muscle is not highly disturbed by excessive repetitive intake of MSG in healthy man.
... However, MTX treated animals did not differ much from the control group. The accumulation of formate rather than methanol is itself considered to cause methanol toxicity [44]. A significant loss in body weight was observed in methanol-exposed rats [45]. ...
The use of the artificial sweetener aspartame has long been contemplated and studied by researcher around the world regarding their varying negative effects. The present study aims to evaluate the long-term effect of aspartame (75 mg/kg) on liver and brain antioxidant status with histopathological changes in liver and renal cortex in Wistar strain albino rats. Many existing reports, which are available, state that aspartame releases toxic metabolites during metabolism, in which methanol is considered to be one. To mimic the human methanol metabolism, methotrexate (MTX) treated rats were included to study the aspartame effects. There were significant decrease in reduced glutathione (GSH), glutathione reductase (GR) along with marked increase in lipid peroxidation (LPO), glutathione-S-transfrease (GST), γ-glutamyl transpeptidase (γ-GT), protein carbonyl and formate level, indicating changes in the antioxidant status of liver and brain. There were also significant histological changes in the liver and renal cortex. Hence, methanol per se and its metabolites may be responsible for the antioxidant status and histological changes in liver and renal cortex. Hence, it can be concluded that long-term aspartame may be responsible for oxidative stress and the hepato-renal toxicity.
... After being ingested, aspartame is completely metabolized into its primary constituents, i.e. aspartic acid, phenylalanine and methanol. After absorption, methanol is carried to the liver through the portal circulation and is metabolized there to formaldehyde, a highly reactive and toxic substance which, among others, may cause blindness (DAVOLI et al., 1986;LEON et al., 1989;STEGINK et al., 1989;TROCHO et al., 1998). TROCHO and co-workers (1998) reported the formation of adducts by the binding of formaldehyde produced by aspartame injection to proteins and DNA. ...
Methanol is an alcohol which is metabolized to folmaldehyde in humans. It is a very toxic substance, responsible for blindness in cases of methanol intoxication. This study shows the production of methanol when aspartame is used to sweeten coffee brew. The temperature versus pH binomium was also tested. When assayed at 90 °C coffee brew+aspartame and aspartame solution showed an increase in methanol release of 17.8 and 19.3%, respectively, as compared with coffee brew. At 180 °C, the increase was 32.5 and 26.3%, respectively. Our data revealed a protective effect of the pH of coffee on
the degradation of aspartame and formation of methanol; an important fact, mainly for specific populations that use aspartame, like diabetics.
... Both methanol and formate are endogenous chemicals with body burdens arising from dietary sources and metabolic processes. Methanol is available in the diet from the ingestion of fruits, fruit juices, alcoholic beverages, and certain vegetables, as well as from the gastrointestinal hydrolysis of the artificial sweetener, aspartame (10% methanol by weight; Stegink et al., 1989). Methanol is generated metabolically by the action of a methyltransferase system, although other enzymatic pathways likely contribute to endogenous levels. ...
A physiologically based pharmacokinetic (PBPK) model was developed for the monkey, to account for fractional systemic uptake of inhaled methanol vapors in the lung. Fractional uptake of inhaled [14C]-methanol was estimated using unreported exhaled breath time course measurements of [14C]-methanol from the D.C. Dorman et al. (1994, Toxicol Appl Pharmacol. 128, 229-238) lung-only exposure study. The cumulative amount of [14C]-methanol exhaled was linear with respect to exposure duration (0.5 to 2 h) and concentration (10 to 900 ppm). The model estimated that forty to eighty-one percent of the of inhaled [14C]-methanol delivered to the lung was taken into systemic circulation in female Cynomolgus monkeys exposed for two h to 10-900 ppm of [14C]-methanol. There was no apparent trend between the percent of inhaled [14C]-methanol absorbed systemically and the [14C]-methanol exposure concentration. Model simulations were conducted using a single saturable Michaelis-Menten equation with Vmaxc, the metabolic capacity set to 15.54 mg/kg/h and Km, the affinity constant, to 0.66 mg/l. The [14C]-methanol blood concentrations were variable across [14C]-methanol exposure groups and the PBPK model tended to over-predict systemic clearance of [14C]-methanol. Accounting for fractional uptake of inhaled polar solvents is an important consideration for risk assessment of inhaled polar solvents.
... 35 There are also a number of health concerns with regard to consumption of artificial sweeteners. 36 ...
In recent years there has been increased interest in the role of commercial soft drinks in dental diseases namely as dental caries and erosion. The objective of this paper has been to review the past and current literature to determine the present knowledge on this subject. The literature related to dental caries, erosion, drinks, soft drinks and fruit juices was reviewed. The literature shows efforts have been taken to modify soft drinks by either adding or deleting certain components so as to reduce their harmful effects on teeth. A rational protocol to encourage the sensible use of drinks and the modification of drinks to render them less harmful would be advisable.
Aspartame is a low-calorie sweetener that has been used for decades in place of sugar. However, there has been conflicting reports on the use and safety profile of aspartame associated with several diseases especially cancer and cardiovascular diseases. This study therefore aims to determine the effects of aspartame on some cardiovascular indices. Thirty seven (37) young Albino Wistar rats weighing between 110g-140g were used for this study. The rats were divided into five groups; control (5) received 5 ml of distilled water. Group 1 (n=8) received 5 ml of diet soda, group 2 (n=8) received 5 ml diluted (1:1) diet soda, Group 3 (n=8) received 5 ml aspartame 45 mg/kg b.w, Group 4 (n=8) received 5 ml of aspartame 22.5 mg/kg b.w. The various doses of aspartame and diet soda were administered orally daily for ten weeks. Weight of the rats were taken weekly, at the end of the experimental period, the rats were sacrificed and blood samples collected into plain sample bottles and tri sodium citrate bottles. Lipid profile (total cholesterol, HDL-C, LDL-C and triglyceride) were analyzed spectrophotometrically, fibrinogen and blood viscosity were also measured. Results showed that the aspartame and diet soda significantly increased total cholesterol, triglyceride, LDL-C, fibrinogen and plasma viscosity and significantly decreased HDL cholesterol. In conclusion, consumption of aspartame as a sweetener can impact negatively on cardiovascular haemodymic factors. Therefore, its intake should be discouraged.
Background & Objective
Aspartame, (L-aspartyl-L-phenylalanine methyl ester) is a widely used artificial sweetener but studies raise safety concerns regarding the use of aspartame metabolites especially methanol. In this review, we aimed to provide mechanistic insights that may explain aspartame-induced immune dysregulation.
Findings
While evidence is limited, from the available literature, possible mechanisms for immune dysfunction associated with aspartame include (1) alterations in bidirectional communication between neuro-immune-endocrine responses (2) disruption of the brain-gut-microbiota-immune axis (3) induction of oxidative stress in immune cells and organs and lastly (4) the immune-activation effect of methanol.
Conclusion
Further studies are needed to confirm above proposed mechanisms that may explain aspartame- induce immune dysregulation.
Manuscript History: The objective of the present study is to explore the synergic and the presumable protective effects of the combination of N-acetyl cysteine (NAC) and folic acid (FA) against aspartame induced nephrotoxicity. Eighteen adult male Wistar rats, weighing 150-170 g, were randomly divided into three groups as follows: first group was given distilled water and served as control group; the seconed group was given aspartame dissolved in distilled water in a dose of 500 mg /kg b.wt.; the third group was given both NAC and folic acid dissolved in distilled water in a dose of 600 mg /kg b.wt. and 12 mg/kg b.wt. respectively. The experimental period was carried out for 42 days. Serum urea, creatinine, and potassium were significantly increased whereas sodium and calcium were significantly decreased in rats that had received aspartame. Blood hemoglobin (Hb), serum iron (Fe) and ferritin were significantly decreased whereas serum total iron binding capacity (TIBC) and unsaturated iron binding capacity (UIBC) were significantly increased.The concentration of reduced glutathione (GSH), and the activity of glutathione peroxidase (Gpx), and catalase (CAT) were significantly decreased whereas the concentration of LPO (TBARS) in kidney tissues was significantly increased. Combined Treatment with NAC and FA significantly restored kidney functions, modulate hematological parameters, reduced lipid peroxidation and enhanced reduced glutathione level. Copy Right, IJAR, 2014,. All rights reserved.
Aspartame, an artificial sweetener is very widely used in many foods and beverages. But there are controversies about its metabolite which is marked for its toxicity. Hence it is believed to be unsafe for human use. Previous studies have reported on methanol exposure with involvements of free radicals on excitotoxicity of neuronal apoptosis. Hence, this present study is proposed to investigate whether chronic aspartame (FDA approved Daily Acceptable Intake (ADI),40 mg/kg bwt) administration could release methanol, whether it can induce changes in brain oxidative stress status and gene and protein expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax and caspase-3 in the rat brain region. To mimic the human methanol metabolism, methotrexate (MTX)-treated Wistar strain male albino rats were used and after the oral administration of aspartame, the effects were studied along with controls and MTX-treated controls. Aspartame exposure resulted with a significant increase in the enzymatic activity in protein carbonyl, Lipid peroxidation levels, Superoxide dismutase, Glutathione-S-Transferase, Glutathione peroxidase and Catalase activity in (Aspartame MTX)-treated animals and with a significant decrease in reduced Glutathione, Glutathione reductase and protein thiol, pointing out the generation of free radicals. The gene and protein expression of pro apoptotic marker Bax showed a marked increase whereas the anti-apoptotic marker Bcl-2 decreased markedly indicating the aspartame is harmful at cellular level. It is clear that long term aspartame exposure could alter the brain antioxidant status, and can induce apoptotic changes in brain.
Interest has developed in the use of urinary formic acid as a biologic exposure index of occupational methanol exposure. Four human subjects were exposed to approximately 200 ppm of methanol in a test chamber for 6 hours. Ambient air in the chamber was monitored for methanol, while urine was monitored for formic acid. Urine specimens were collected immediately before, immediately after, and 16 hours following cessation of exposure to methanol. Mean urinary formic acid was increased from baseline at the end of the exposure session (though not significantly), but had returned to baseline in samples collected 16 hours following cessation of exposure. These results suggest that measurement of urinary formic acid in specimens collected 16 hours following cessation of exposure to methanol may not be an appropriate approach to biologically assess methanol exposure.
Biological monitoring of exposure to industrial chemicals commonly involves laboratory analyses of a toxicant or metabolites in urine. The American Conference of Governmental Industrial Hygienists has recommended biological exposure indices for methanol exposure based on methanol and formate in urine. The present study was designed primarily to evaluate methanol in urine and other potential biological determinants of methanol exposure. Volunteer subjects underwent controlled exposure to methanol vapor at different concentrations for approximately 8 hours to simulate a standard work shift. Urine was collected immediately prior to exposure sessions, during exposures, and immediately following cessation of exposures. Samples were analyzed for methanol, formate, specific gravity (SpGr), and creatinine. The following biological determinants were examined: total methanol excreted during the shift; mean concentration of methanol excreted during the shift (uncorrected, and corrected for SpGr and creatinine); and concentration of methanol and formate excreted in urine immediately following cessation of exposure (again uncorrected, and corrected for SpGr and creatinine). All methanol-based parameters were approximately linearly related to exposure concentration, but the results for formate related poorly to exposure. In addition, there was considerable interindividual variation in all measured parameters. Overall, measurement of formate in urine was not a useful indicator of individual or group methanol exposures in the range of the permissible exposure limit of 200 ppm. Because of large interindividual variation, methanol in urine (i.e., concentration at end of shift or mean concentration excreted across shift) would not appear suitable for quantitative assessment of individual exposures, but methanol in urine would appear useful as a semiquantitative or qualitative index of individual exposure, or to assess quantitatively the methanol exposure of a group.
Five human subjects were exposed to an atmosphere containing 200 ppm of methanol in a test chamber for 7 hours per day for 5 consecutive days (Monday through Friday). Ambient air in the chamber was monitored continuously for methanol, while urine was monitored for methanol and formic acid. Spot urine specimens were collected immediately before and immediately after exposure periods on Monday through Friday, and also on the Saturday and Sunday mornings following the week of exposure. Morning urine specimens obtained Tuesday through Saturday were collected approximately 16 hours following cessation of exposure on the preceding day. Mean urinary methanol concentrations were increased from baseline at the end of each exposure session (Monday through Friday), but had returned to baseline in samples collected 16 hours following cessation of exposure. The concentration of formic acid in morning urine specimens did not change significantly over the 7 days of this experiment. These results indicate that: 1 there is no day-to-day accumulation of formic acid in urine in conjunction with five consecutive days of near-maximal permissible airborne methanol exposure; and 2 measurement of formic acid in urine specimens collected 16 hours following cessation of exposure does not appear to reflect inhalational methanol exposure on the preceding day.
Sugar-free or reduced-sugar foods and beverages are very popular in the United States and other countries, and the sweeteners that make them possible are among the most conspicuous ingredients in the food supply. Extensive scientific research has demonstrated the safety of the 5 low-calorie sweeteners currently approved for use in foods in the United States–acesulfame K, aspartame, neotame, saccharin, and sucralose. A controversial animal cancer study of aspartame conducted using unusual methodology is currently being reviewed by regulatory authorities in several countries. No other issues about the safety of these 5 sweeteners remain unresolved at the present time. Three other low-calorie sweeteners currently used in some other countries–alitame, cyclamate, and steviol glycosides–are not approved as food ingredients in the United States. Steviol glycosides may be sold as a dietary supplement, but marketing this product as a food ingredient in the United States is illegal. A variety of polyols (sugar alcohols) and other bulk sweeteners are also accepted for use in the United States. The only significant health issue pertaining to polyols, most of which are incompletely digested, is the potential for gastrointestinal discomfort with excessive use. The availability of a variety of safe sweeteners is of benefit to consumers because it enables food manufacturers to formulate a variety of good-tasting sweet foods and beverages that are safe for the teeth and lower in calorie content than sugar-sweetened foods.
It has been hypothesized that the dietary sweetener aspartame (L-aspartyl-L-phenylalanine methyl ester) might promote seizures and this hypothesis has been argued in the published literature. The current manuscript reviews the biochemical, neurochemical and behavioral experiments that have been carried out in order to assess the hypothesis linking aspartame with seizure promotion. We conclude that convulsive seizures are not caused by orally administered aspartame in rodents or in primates, including humans. Early reports of seizure facilitation by aspartame in several rodent models were not confirmed by later and more careful experimentation. Proconvulsive effects were absent in humans and other mammals with epilepsy and those without epilepsy. Lack of convulsive liability was evident, even when doses many fold higher than those consumed in the human diet, were used in experimental paradigms. Studies of aspartame in absence seizures are not as complete as those in convulsive seizures, but available evidence in humans does not document an association between absence seizure incidence and aspartame usage.
This article discusses the acceptable daily intake (ADI) and the postmarketing surveillance of consumption levels for a food additive, using the widely used food additive aspartame (APM, L-aspartyl-L-phenylalanine methyl ester) as an example. The safety implications of the ADI and consumption levels are also discussed. Aspartame has been assigned an ADI of 40 mg/kg/day by the World Health Organization and regulatory authorities in Europe and Canada, and of 50 mg/kg/day by the US Food and Drug Administration. A number of different methods have been used to measure consumption levels of food additives. Consumption estimations for aspartame from one such method, the food intake survey, have been done in the United States, Canada, Germany, and Finland. APM consumption in all age groups and selected subpopulations, even at the 90th percentile, is approximately 2-10 mg/kg/day and is thus well below the ADI.
Six human males each received 0.56 g phenylalanine (Phe) in the form of 1.0 g aspartame or 12.2 g bovine albumin in 200 ml water or water alone. Venous blood samples collected before consumption and during the following 4 hr were assayed for plasma levels of large, neutral amino acids (LNAA), aspartate, insulin and glucose. The area under the curve for plasma Phe was 40% greater, although not significant, after aspartame compared with albumin intake. The indicated increased clearance rate of plasma Phe after albumin may be caused by the significant increase of insulin, on which aspartame had no effect. There was a significant main effect of aspartame for plasma tyrosine but not for tryptophan, valine, isoleucine or leucine. Plasma aspartate was significantly increased at 0.25 hr after the aspartame intake. The percentage Phe/LNAA decreased slightly in response to albumin but increased 55% after aspartame and remained significantly increased for 2 hr. Tyrosine/LNAA increased and tryptophan/LNAA decreased modestly after aspartame intake. The study showed that the intake of aspartame in a not unrealistically high dose produced a marked and persistent increase of the availability of Phe to the brain, which was not observed after protein intake. The study indicated, furthermore, that Phe was cleared faster from the plasma after consumption of protein compared with aspartame.
Plasma amino acid concentrations were measured and selected amino acid ratios were calculated in 12 normal adults and 12 adults heterozygous for phenylketonuria (PKU) ingesting a hamburger and milk shake meal providing 1 g protein/kg body wt. Plasma concentrations of all amino acids increased significantly over baseline after meal ingestion in both groups, reaching the highest mean values 3-5 h after meal ingestion. Plasma phenylalanine concentrations were significantly higher in heterozygous than in normal subjects both before and at all times after meal ingestion. The absolute increase in plasma phenylalanine concentration over baseline and the area under the plasma phenylalanine concentration-time curve were approximately twice as large in heterozygous as in normal subjects. However, the molar ratio of the plasma phenylalanine concentration to the sum of the plasma concentrations of the other large neutral amino acids did not increase significantly over baseline, but rather decreased.
Twelve normal adult subjects ingested a beverage providing 0.136 mmol aspartame/kg body wt on 2 different days. On 1 study day the beverage provided only aspartame, on the other the beverage provided both aspartame and 3.51 mmol sucrose/kg body wt. The high mean plasma phenylalanine concentrations were similar after administration of aspartame alone (158 +/- 28.9 mumol/L, mean +/- SD) and administration of aspartame plus sucrose (134 +/- 44.1 mumol/L). Evaluation of the area under the plasma concentration-time curve (AUC) for phenylalanine also showed no significant difference between groups (197 +/- 49.1 vs 182 +/- 28.3 mumol.L-1.h for aspartame alone and aspartame plus sucrose, respectively). Similarly, the high mean ratio of phenylalanine to large neutral amino acids (Phe:LNAA) in plasma did not differ significantly (0.265 +/- 0.046 for aspartame alone, 0.275 +/- 0.107 for aspartame plus sucrose). However, there was a small but significant difference between groups for the 4-h AUC values for plasma Phe:LNAA. The simultaneous ingestion of sucrose with aspartame had only minor effects on aspartame's metabolic disposition.
Six adults heterozygous for phenylketonuria (PKU) ingested eight successive servings of unsweetened and aspartame (APM)-sweetened beverage at 1-hour intervals in a randomized, balanced, crossover design. In one part, the eight beverage servings were not sweetened. In the other, each of the eight beverage servings provided 600 mg of APM, a dose equivalent to the amount provided by 36 oz of an APM-sweetened diet beverage. Plasma aspartate concentration was not significantly increased after ingestion of unsweetened or APM-sweetened beverage. Similarly, ingestion of the unsweetened beverage had no significant effect on plasma phenylalanine concentration. However, ingestion of APM-sweetened beverage significantly increased plasma phenylalanine concentrations 2.35 to 4.03 mumol/dL above baseline 30 minutes after ingestion. Plasma phenylalanine values reached a steady-state after administration of five servings of APM-sweetened beverage and were slightly, but significantly higher than usual postprandial values for adults heterozygous for PKU. Similarly, the ratio of the plasma phenylalanine concentration to the sum of the concentration of the large neutral amino acids was significantly higher than usual postprandial values. Blood methanol and formate concentrations remained within normal limits. These data indicate that a fasting adult heterozygous for PKU could consume the equivalent of 24 12-oz servings of APM-sweetened beverage over an 8-hour period and only increase plasma phenylalanine concentration to a modest degree.
Large-scale use of methanol (MeOH) as an automotive fuel may increase exposure of the public to MeOH vapor, necessitating the need for additional data for an adequate human health risk assessment. Formate is accepted as the toxic metabolite of MeOH, its metabolism is folate-dependent, and potentially sensitive folate-deficient subpopulations (e.g., pregnant women) exist that may be at higher risk to low-level methanol exposure. This study determined the pharmacokinetics of [14C]MeOH and [14C]formate in normal and folate-deficient (FD) monkeys following inhalation of environmentally relevant concentrations of [14C]MeOH. Four normal adult female cynomolgus monkeys were anesthetized (isoflurane) and exposed by lung-only inhalation to 10, 45, 200, and 900 ppm [14C]MeOH for 2 hr. Monkeys were then placed on a FD diet until folate concentrations consistent with moderate deficiency (29-107 ng/ml) developed in red blood cells and then reexposed to 900 ppm (900-FD) for 2 hr. Average (+/- SD) end-of-exposure blood [14C]MeOH concentrations were 0.65 +/- 0.3, 3.0 +/- 0.8, 21 +/- 16, 106 +/- 84, and 211 +/- 71 microM, while average (+/- SD) peak blood [14C]formate concentrations were 0.07 +/- 0.02, 0.25 +/- 0.09, 2.3 +/- 2.9, 2.8 +/- 1.7, and 9.5 +/- 4.7 microM following MeOH inhalation at 10, 45, 200, 900, and 900-FD ppm, respectively. The blood concentration of [14C]MeOH-derived formate from all exposures was 10 to 1000 times lower than the endogenous blood formate concentration (0.1 to 0.2 mM) reported for monkeys. These results suggest that low-level exposure to MeOH would not result in elevated blood formate concentrations in humans under short-term exposure conditions.
Aspartame is a methyl ester of a dipeptide used as a synthetic nonnutritive sweetener in over 90 countries worldwide in over 6000 products. The purpose of this investigation was to review the scientific literature on the absorption and metabolism, the current consumption levels worldwide, the toxicology, and recent epidemiological studies on aspartame. Current use levels of aspartame, even by high users in special subgroups, remains well below the U.S. Food and Drug Administration and European Food Safety Authority established acceptable daily intake levels of 50 and 40 mg/kg bw/day, respectively. Consumption of large doses of aspartame in a single bolus dose will have an effect on some biochemical parameters, including plasma amino acid levels and brain neurotransmitter levels. The rise in plasma levels of phenylalanine and aspartic acid following administration of aspartame at doses less than or equal to 50 mg/kg bw do not exceed those observed postprandially. Acute, subacute and chronic toxicity studies with aspartame, and its decomposition products, conducted in mice, rats, hamsters and dogs have consistently found no adverse effect of aspartame with doses up to at least 4000 mg/kg bw/day. Critical review of all carcinogenicity studies conducted on aspartame found no credible evidence that aspartame is carcinogenic. The data from the extensive investigations into the possibility of neurotoxic effects of aspartame, in general, do not support the hypothesis that aspartame in the human diet will affect nervous system function, learning or behavior. Epidemiological studies on aspartame include several case-control studies and one well-conducted prospective epidemiological study with a large cohort, in which the consumption of aspartame was measured. The studies provide no evidence to support an association between aspartame and cancer in any tissue. The weight of existing evidence is that aspartame is safe at current levels of consumption as a nonnutritive sweetener.
Water intoxication is a serious problem in many patients with chronic psychiatric illness. In an effort to determine the mechanism of this disorder, we investigated the osmoregulation of water intake and antidiuretic function in psychiatric patients with polydipsia and hyponatremia and in matched controls with psychiatric illness but neither polydipsia nor hyponatremia. We found that a water load suppressed plasma osmolality and vasopressin and urine osmolality in both groups, but that urinary dilution and free water clearance were impaired in the patients with hyponatremia, even though plasma levels of vasopressin and solute clearance were similar in the two groups. Moreover, during water loading and infusion of hypertonic saline, the plasma level of vasopressin was higher at any given plasma osmolality in the test patients than in the controls, indicating a downward resetting of the osmostat. Patients' estimates of the amount of water they desired were shown to correlate significantly with the amount of water consumed and, at any given level of plasma osmolality, appeared to be higher in the test patients than in the controls. We conclude that psychiatric patients with polydipsia and hyponatremia have unexplained defects in urinary dilution, the osmoregulation of water intake, and the secretion of vasopressin.
1. A micromethod for the determination of amino acids by ion exchange chromatography was applied to the quantitative determination of the free amino acids in 0.1 ml of plasma of the newborn infant. The precision of the method was in general within the range ± 5%. An interpretive analysis of a typical chromatogram is given.
2. Plasma was best stored at -68°C pending analysis; errors likely to arise on storage at -20°C and higher temperatures are pointed out. Some errors likely to arise in the preparation and storage of plasma protein free filtrates are also indicated.
3. Comparison of the free amino acids in the femoral vein plasma of 25 newborn infants was made with the literature values of the free amino acids in the plasma of adults. The differences noted were not great, but were apparently characteristic. On comparing heel puncture plasma, some amino acids were higher than in femoral vein plasma, but it was concluded that heel puncture plasma would be satisfactory for routine clinical purposes. Some possible sources of error which might explain the elevated amino acids in the heel puncture plasma were noted.
4. On comparison of newborn with 3-day-old infants, some changes in amino acid levels were noted. The changes were not great, but seemed to be characteristic and consistent.
5. A number of small peaks which have not been noted previously in plasma have been indicated on the chromatogram. They were not identified, but were mentioned to draw attention to the possibilities of hitherto unrecognized ninhydrin-positive components of plasma.
We have determined the effects of aspartame (APM) ingestion by humans on plasma free phenylalanine concentration in a variety of feeding situations. These clinical studies have examined the plasma phenylalanine response when APM was given as a bolus dose in unsweetened beverage, orange juice, a sucrose solution, capsules, or a slurry or as part of a meal. The complexity of the meal feedings ranged from soup and a beverage to a hamburger and a milk shake.
A gas chromatographic procedure is described for the simultaneous, quantitative, microdetermination of ethanol, methanol,
isopropanol, acetaldehyde and acetone. By utilizing a column containing the polymer, Porapak Q, and interchangeable glass
inlets, complete separation of these volatiles is achieved and whole blood may be directly injected without prior processing.
This provides a simple, rapid, precise method for the determination of these toxic substances in the clinical and research
laboratory.
Abstract— The brain levels of each of the aromatic and branched-chain amino acids change 2 h after fasting rats begin to consume either a carbohydrate-fat diet or a similar diet containing 18% or 40% protein. Carbohydrate-fat ingestion elevates the concentrations of each of the aromatic amino acids in brain, while substantially depressing those of the branched-chain amino acids. The inclusion of protein in this diet suppresses the increases in brain aromatic amino acids and attenuates the decreases in the branched-chain amino acids. The changes in the brain level of each neutral amino acid following the ingestion of any of these diets correlate extremely well with the effects of the diet on the serum neutral amino acid pattern, specifically on the serum concentration ratio of each neutral amino acid to the sum of the other neutral amino acids. The diet-induced changes in the brain level of each of the amino acids also correlate surprisingly well with the calculated rate of brain influx for each amino acid.
A sensitive and specific assay for formic acid in body fluids has been developed. The assay is based on the reaction of formate with bacterial formate dehydrogenase coupled to a diaphorase-catalyzed reduction of the nonfluorescent dye resazurin to the fluorescent substance resorufin. Formate concentrations of 0.5 μg/ml of reaction mixture can be accurately measured. Small volumes of body fluids can be used for the analysis of both methanol and formate. The procedure described is simple and allows for the economical and rapid determination of formate. It can be used in studies concerned with the disposition of formate, as it relates to methanol metabolism. Also, it may be useful in studies where formate might exist as a metabolic intermediate of certain drugs or chemicals.
Aspartame (3-amino-N-(alpha-carboxyphenethyl) succinamic acid, methyl ester; the methyl ester of aspartylphenylalanine, SC-18862) is hydrolyzed in the gut to yield aspartic acid, phenylalanine, and methanol. This review of the literature describes the metabolic paths followed by aspartate in its conversion to CO2 or its incorporation into body constituents. About 70 percent of 14C from [asp-14C]-aspartame is converted in the monkey to 14CO2. Some of the aspartate is converted at the intestinal mucosal level to alanine by decarboxylation. This amino acid may be oxidized to CO2 by entering the tricarboxylic acid cycle via pyruvate and acetyl CoA. In addition, transamination of aspartate to oxaloacetate permits this product also to enter the tricarboxylic acid cycle. Aspartate may also be incorporated into body constitutents such as other amino acids, proteins, pyrimidines, asparagine, and N-acetylaspartic acid. It is concluded that the aspartate moiety of aspartame is metabolized in a manner similar to that of dietary aspartic acid.
The effect of varying dietary protein content on the daily rhythms in plasma neutral amino acid concentrations was studied in patients with chronic cirrhosis. For two consecutive 5-day periods, subjects consumed diets containing either 0 or 75 g of protein per day. Blood samples were drawn at 4-hr intervals on the 4th and 5th days of each dietary period. For most of the neutral amino acids, the changes in plasma concentration associated with time of day or with variations in dietary protein content were similar to those observed previously in normal subjects. Ingestion of the protein-free diet caused significant reductions in the daytime level of all amino acids studied, except for tryptophan, the concentration of which did not change during the 24-hr period. Ingestion of the 75-g protein diet caused plasma levels of most of theamino acids to increase slightly during the day; these increments were not statistically significant for tryptophan, tyrosine, leucine, and methionine. The absolute plasma concentrations of most of the neutral amino acids were also in the normal range; exceptions included methonine, tyrosine, and phenylalanine, whose plasma levels were significantly elevated above normal valves. The plasma ratios of tryptophan, tyrosine, and phenylalanine concentrations to the sum of the concentrations of other large neutral amino acids increased during the day uhen the protein-free diet was ingested; this effect was moderated by the addition of protein to the food. The plasma ratios for the branched-chain amino acids were depressed below normal; those for tyrosine, phenylalanine, and methionine were significantly increased. The plasma tryptophan ratio was within the normal range. These findings provide a basis for anticipating that the uptake from blood into brain of several of the large neutral amino acids may be modified in patients with chronic cirrhosis.
The effect of dietary protein content on the diurnal variations in plasma neutral amino acid levels was studied in normal human subjects. For three consecutive 5-day periods, subjects consumed diets containing 0, 75, or 150 g of egg protein per day. Blood samples were drawn at 4-hr intervals on the 4th and 5th days of each period. Consumption of the protein-free diet caused plasma concentrations of all amino acids studied to fall in the late morning and afternoon, while the 150-g protein diet elicited increases in these levels during the daytime. Ingestion of the diet containing 75 g of egg protein tended to diminish the amplitudes of the daily rhythms in plasma amino acid levels, but most amino acids still exhibited small but significant elevations late in the evening. At all times of day, plasma concentrations of the large neutral amino acids studied (i.e., aromatic and branched-chain amino acids, and methionine) varied directly with the protein content of the diet. In contrast, the relationships between dietary protein content and the plasma concentrations of glycine and alanine, two small neutral amino acids, were inverse. The ratios of plasma tryptophan, tyrosine, and phenylalanine levels to the sum of the concentrations of other large neutral amino acids tended to fall as the protein content of the diet was increased. The corresponding ratio for valine increased as protein was added to the diet, while the leucine and isoleucine ratios were not correlated with dietary protein content. Since diet-induced changes in plasma trypotphan and tyrosine ratios in animals are known to cause parallel alterations in brain tryptophan and tyrosine levels, and thus in the rates of brain serotonin and catecholamine synthesis, our data suggest that ingestion of carbohydrates and protein may also normally affected brain monoamine synthesis in humans.
Aspartame [SC-18862; 3-amino-N-(alpha-carboxyphenethyl) succinamic acid, methyl ester, the methyl ester of aspartylphenylalanine] is a sweetening agent that organoleptically has about 180 times the sweetness of sugar. The metabolism of aspartame has been studied in mice, rats, rabbits, dogs, monkeys, and humans. The compound was digested in all species in the same way as are natural constituents of the diet. Hydrolysis of the methyl group by intestinal esterases yielded methanol, which was oxidized in the one-carbon metabolic pool to CO2. The resultant dipeptide was split at the mucosal surface by dipeptidases and the free amino acids were absorbed. The aspartic acid moiety was transformed in large part to CO2 through its entry into the tricarboxylic acid cycle. Phenylalanine was primarily incorporated into body protein either unchanged or as its major metabolite, tyrosine.
Aspartame is a dipeptide (L-aspartyl-L-phenylalanyl-methyl ester) with a sweeting potential 180 to 200 times that of sucrose. Questions have been raised about potential toxic effects of its constituent amino acids, aspartate and phenylalanine when the compound is ingested in large amounts. Plasma and erythrocyte amino acid levels were measured in 12 normal subjects after administration of either Aspartame (34 mg/kg) or equimolar quantities of aspartate (13 mg/kg) in a crossover design. No changes in either plasma or erythrocyte aspartate levels were noted at any time after either Aspartame or aspartate ingestion. Plasma phenylalanine levels decrease slightly after aspartate loading, and increased from fasting levels (4.9 +/- 1 mumoles/100 ml) to 10.7 +/- 1.9 mumoles/100 ml about 45 to 60 minutes after Aspartame loading. Phenylalanine levels returned to baseline by 4 hours. Erythrocyte phenylalanine levels showed similar changes.
The rates at which monoaminergic neurons in rat brains synthesize their neurotransmitters depend on the availability of the amino acid precursors tryptophan (for serotonin) and tyrosine (for dopamine and norepinephrine). The administration of tryptophan, the injection of insulin, or the consumption of a single protein-free high-carbohydrate meal all elevate brain tryptophan levels and, soon thereafter, the levels of serotonin and its major metabolite 5-hydroxyindole acetic acid. The addition of protein to the meal suppresses the increases in brain tryptophan and serotonin, because protein contributes to plasma considerably larger amounts of the other neutral amino acids (e.g., leucine, phenylalanine) than of tryptophan, and these other amino acids compete with tryptophan for uptake into the brain. The elevation of brain tyrosine (by injection of the amino acid or consumption of a single 40% protein meal) accelerates brain catecholamine synthesis, as estimated by measuring brain dopa accumulation after decarboxylase inhibition, or brain catecholamine accumulation after inhibition of monoamine oxidase. These observations suggest that serotonin- and catecholamine-containing brain neurons are normally under specific dietary control.
1. This paper describes the results of a survey of the effects of peptides and amino acids on uptake by rings of everted hamster jejunum in vitro of glycylsarcosylsarcosine, a tripeptide which is taken up by an active mechanism but is very resistant to hydrolysis, appearing intact in the rings. The results of a small number of similar experiments with β-alanylglycylglycine, another tripeptide which is taken up with very little hydrolysis, are also described.
2. Uptake of the two tripeptides was inhibited by other di- and tri-peptides, but not by free amino acids. The results suggest that dipeptides and tri-peptides share a common uptake mechanism. The tetrapeptide glycylsarcosylsarcosylsarcosine did not inhibit uptake of glycylsarcosylsarcosine, and appears to be unable to utilize the uptake mechanism.
3. The results add to information about the influence of molecular structure on intestinal uptake of peptides by the system used by glycylsarcosylsarcosine, which is shared by a wide range of other di- and tri-peptides. In conjunction with previous results, they suggest that substitution of the N-terminal amino or C-terminal carboxyl groups reduces affinity for transport, that the presence of a β-amino acid residue in a peptide is tolerated by the transport system, and that the presence of a d-amino acid residue reduces affinity for transport. Some peptides containing or made up of basic or acidic amino acid residues appear to have a low affinity for the transport system used by glycylsarcosylsarcosine.
4. Of two biologically active peptides, one, cephalexin, a peptide antibiotic, inhibited uptake of glycylsarcosylsarcosine and is probably transported by the same system. The other, prolylleucylglycineamide, which has the action of a hypothalamic regulatory factor, did not, and its structural features may make it unsuitable for carrier-mediated transport by the small intestine.
The effect of MSG ingestion in consomme on the plasma glutamate concentration response was studied in normal adult subjects. In the first study nine subjects ingested three different consomme servings (providing 0, 25 and 50 mg/kg body weight MSG) in a Latin square design. Plasma glutamate concentrations were not significantly increased over baseline (3.69 +/- 1.08 mumol/dl) when no added MSG was present. However, mean peak plasma glutamate levels increased proportional to dose when MSG was added (10.2 +/- 2.00 and 17.0 +/- 8.06 mumol/dl at 25 and 50 mg/kg body weight respectively). Since six of the nine subjects in this study reported an idiosyncratic symptom response when tested with MSG at 150 mg/kg body weight, nine additional subjects were also studied. They ingested consomme providing MSG at 0 and 50 mg/kg body weight. No significant differences in plasma amino acid responses were noted between the two groups of subjects.
More than 100 years ago, Claude Bernard recognized the importance of a constant internal environment to the survival of living organisms. Almost 50 years have elapsed since Homer Smith assigned a central role to the kidneys in this critical process, describing them as "the master chemists of our internal environment."1 This is no exaggeration, since in the evolutionary process the adaptation of life initially to fresh water and much later to an arid terrestrial environment is closely linked with the kidney's ability to elaborate urine that is either more dilute or more concentrated than body fluids. The concentration of osmotically . . .
Aspartame (APM) is a dipeptide sweetener (L-aspartyl-L-phenylalanine methyl ester). It has been suggested that excessive use of the product might elevate plasma aspartate and phenylalanine concentrations. Eight normal adults (four male, four female) ingested three successive 12-oz servings of APM-sweetened beverage at two-hour intervals. The study was carried out in two parts in a randomized cross-over design. In one study the beverage was not sweetened. In the other, the beverage provided 10 mg APM/kg body weight per serving. Plasma amino acid concentrations were measured throughout the six-hour study period. The addition of APM to the beverage had no significant effect on plasma aspartate concentration. APM addition did increase plasma phenylalanine levels 1.64 to 2.05 mumol/dL above baseline values (5.09 +/- 0.82 mumol/dL) 30 to 45 minutes after each dose. However, plasma phenylalanine levels did not exceed normal postprandial values at any time. The data indicate ready metabolism of APM's amino acid content when administered at levels likely to be ingested by individuals who are heavy users of such beverages.
Aspartame [Nutrasweet, Equal (Searle Consumer Products, Chicago, Ill.)] is the methyl ester of the dipeptide aspartylphenylalanine (Asp-Phe). After hydrolysis of the ester bond in the intestinal lumen, the dipeptide is apparently absorbed and digested in the same manner as dipeptides derived from protein digestion. We observed that Asp-Phe is hydrolyzed approximately equally well by three previously reported brush border dipeptidases. However, these enzymes have very low affinity for Asp-Phe, and a substantial amount of the dipeptide may be transported intact and hydrolyzed in the cytosol. Starch gel electrophoresis and ion-exchange chromatography of the cytosol of intestinal mucosa and of red blood cell lysate revealed only one peak with Asp-Phe hydrolase activity. This activity was distinct from the seven cytosolic peptidases that have been described previously. The reduction in Asp-Phe hydrolase activity in the brush border and cytosol of diseased intestinal mucosa was similar to the reduction in levels of other brush border and cytosol enzyme activities. If double-blind studies confirm that some people have symptoms caused by aspartame ingestion, it would be appropriate to test such individuals for deficiency of cytosolic Asp-Phe hydrolase activity.
Recent government publications have indicated that more than 50% of the U.S. population consumes carbonated soft drinks and that use of soft drinks has increased considerably during the past 15 years. In light of these observations, it is important for dietitians to have knowledge about who these carbonated soft drink consumers are, how much of the beverages they are likely to consume, and when and where.
Aspartame (SC-18862, 3-amino-N-(a-carboxyphenethyl)succinarnic acid, methyl ester; the methyl ester of aspartyl-phenylalanine ) is a sweetening agent that organoleptically has about 180 times the sweetness of sugar. Because it so closely resembles naturally occurring dipeptides, it was believed that it would be digested in a similar manner. To show this, the metabolism of (14C) aspartame labeled separately in the methyl, aspartyl and phenylalanine moieties was compared with the metabolism of "C-labeled methanol, aspartic acid, and phenylalanine. The metabolism of each moiety of aspartame was found to be the same as its free counterpart. Parameters measured were: conversion to "COj, incorporation of 14C into plasma proteins, and urinary and fecal excretion of the label. It was concluded that aspartame was digested to its three constituents that were then absorbed as natural constituents of the diet. J. Nutr. 103: 1454-1459, 1973.
This paper describes seemingly trivial variations in the preparation of blood plasma for amino acid analysis, and in the operation of the automatic amino acid analyzer, that can lead to major errors in the quantitative determination of taurine, phosphoethanolamine, the dicarboxylic amino acids, glutamine, the disulphide amino acids, and tryptophan. These technical pitfalls can easily be avoided. The resulting improved accuracy in measurement of plasma amino acids may be essential for meaningful studies of some metabolic or nutritional disorders where differences from normal are subtle.
Protein hydrolysate infusions commonly administered to young infants unable to sustain adequate protein intake contain large amounts of glutamate and aspartate. Neurotoxic effects have been reported in other species and were attributed to high doses of these amino acids. Plasma glutamate and aspartate levels in infants treated with such preparations were within normal limits, but other amino acids were markedly below fasting levels. Plasma amino acid levels quickly reflected the amino acid composition of the hydrolysate and some degree of amino acid imbalance resulted when either of the 2 products employed in this study constituted the sole source of protein intake.
Since methionine is the limiting essential amino acid in soy protein, dl-methionine is often added to infant formulas employing a soy protein base. Urimary excretion of methionine was 5 to 7 times normal in 4- to 13-day-old infants fed such formulas and was 20 times normal in older infants fed such formulas as the sole source of protein. Methionine excretion was directly proportional to the quantity of nitrogen absorbed, and 88 to 93 per cent of excreted methionine had the d configuration. Although plasma methionine levels were not significantly higher than those in infants fed nonfortified diets, 35 per cent of the circulating methionine had the d configuration 2 hours postprandially, and 25 per cent of the plasma methionine had the d configuration 3 to 4 hours postprandially. These data indicate that the young infant fed such formulas had substantial concentrations of d-methionine circulating in the plasma at all times and suggest that tissue amino acid pools may contain substantial quantities of d-methionine.
It has been suggested that aspartame addition to meals already containing large amounts of monosodium L-glutamate would result in an early rapid rise in plasma glutamate and/or aspartate concentrations and increase the potential for dicarboxylic amino acid-induced toxicity. Six normal adult subjects were fed hamburger and milk shake meals providing protein at 1 g/kg body weight in a randomized cross-over design. One meal had no additions while the other contained added monosodium L-glutamate and aspartame (each present at 34 mg/kg body weight). The addition of aspartame plus glutamate had little effect on either plasma or erythrocyte concentrations of glutamate or aspartate beyond those arising from the meal itself. Plasma phenylalanine concentrations were significantly higher (p less than 0.05, paired t test) after ingestion of meals containing aspartame plus glutamate reflecting the increased phenylalanine load.
Methanol metabolism and toxici-ty Aspartame: Physiology and Biochemistry
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Using the menu census survey to estimate dietary intake: Post-market surveillance of aspartame, in Proceed-ings of the International Workshop on Aspartame, session 2, chapter 33
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Principles and procedures of statistics.
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Control of brain neurotransmitter synthesis by precursor availability and nutritional state: Commentary
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Intake of aspartame in 19–50 year old women from the USDA continuing survey of food intakes by individuals (CSFII 85)
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Intestinal metabolism of aspartame and its diketopiperazine and l-phenylalanine methyl ester degradation products
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Canadian approaches to collecting consumption data for chemical substances
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The estimation of intake
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