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Metabolism |
Butchko HH, Stargel WW, Comer CP, Mayhew DA, Benninger C, Blackburn GL, de Sonneville LM, Geha RS, Hertelendy Z, Koestner A, Leon AS, Liepa GU, McMartin KE, Mendenhall CL, Munro IC, Novotny EJ, Renwick AG, Schiffman SS, Schomer DL, Shaywitz BA, Spiers PA, Tephly TR, Thomas JA, Trefz FK.
Metabolism of Aspartame Regul Toxicol Pharmacol. 2002 Apr; 35(2 Pt 2):S17-25.
Numerous studies have evaluated the metabolism of aspartame and the pharmacokinetics of its components - aspartate, phenylalanine, and methanol. Such studies have involved healthy adults, infants, children, and adolescents, PKU heterozygous adults, PKU homozygous individuals, and individuals sensitive to MSG. Studies included acute-dose, repeated-dose, and long-term dose regimens. In healthy adults and children, even after enormous doses, aspartame does not result in plasma concentrations of its components that are of safety concern. Plasma aspartate concentrations remained within the normal range even after bolus doses of aspartame as high as 200 mg/kg. The doses of aspartame used in studies with the other subpopulations have ranged from 4 to 100 mg/kg body wt. Plasma phenylalanine concentrations observed after large-bolus and repeated doses of aspartame were comparable to the normal postprandial range in both healthy adults and PKUH and well below those in untreated PKU. Blood methanol concentrations were not detectable after aspartame doses as high as 34 mg/kg body wt when ingested as a single bolus or about 70 mg/kg body wt when administered as eight divided doses at hourly intervals. Regardless of dose, blood formate concentrations did not change from baseline levels after aspartame administration. Evaluations of urinary formate excretion after single bolus doses of aspartame as high as 200 mg/kg body t demonstrated the body's ability to rapidly metabolize methanol and excrete formate. Thus, even when administered at levels well above 90th percentile average daily consumption, the risk of adverse effects from aspartame or its metabolic components is negligible, strongly supporting the safety of aspartame under its intended conditions of use.
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Oyama Y, Sakai H, Arata T, Okano Y, Akaike N, Sakai K, Noda K.
Cytotoxic effects of methanol, formaldehyde, and formate on dissociated rat thymocytes: a possibility of aspartame toxicity. Cell Biol Toxicol. 2002;18(1):43-50.
Aspartame is a widely used artificial sweetener added to many soft beverages and its usage is increasing in health-conscious societies. Upon ingestion, this artificial sweetener produces methanol as a metabolite. In order to examine the possibility of aspartame toxicity, the effects of methanol and its metabolites (formaldehyde and formate) on dissociated rat thymocytes were studied by flow cytometry. While methanol and formate did not affect cell viability in the physiological pH range, formaldehyde at 1-3 mmol/L started to induce cell death. Further increase in formaldehyde concentration produced a dose-dependent decrease in cell viability. Formaldehyde at 1 mmol/L or more greatly reduced cellular content of glutathione, possibly increasing cell vulnerability to oxidative stress. Furthermore, formaldehyde at 3 mmol/L or more significantly increased intracellular concentration of Ca2+ ([Ca2+]i) in a dose-dependent manner. Threshold concentrations of formaldehyde, a metabolite of methanol, that affected the [Ca2+]i and cellular glutathione content were slightly higher than the blood concentrations of methanol previously reported in subjects administered abuse doses of aspartame. It is suggested that aspartame at abuse doses is harmless to humans.
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Burgert SL, Andersen DW, Stegink LD, Takeuchi H, Schedl HP.
Metabolism of aspartame and its L-phenylalanine methyl ester decomposition product by the porcine gut. Metabolism. 1991 Jun;40(6):612-8.
The intestinal metabolism of aspartame (N-L-alpha-aspartyl-L-phenylalanine methyl ester; APM) and its L-phenylalanine methyl ester (PME) decomposition product was evaluated in six young pigs. Equimolar doses (2.5 mmol/kg body weight) of APM, PME, and L-phenylalanine (PHE) administered to the proximal jejunum produced similar increases in portal blood PHE concentrations. Methanol, nondetectable in portal blood after PHE ingestion, increased markedly after administration of either APM or PME. Portal blood aspartate concentrations were unchanged after PME and PHE administration, but increased significantly after APM administration. Increases in portal blood PHE concentrations were significantly greater than were increases in aspartate concentrations following APM administration. Neither APM, PME, nor aspartyl-phenylalanine (AspPhe) were detected in portal or vena caval blood following administration of any test compound. Steady-state perfusion of the small intestine with APM showed a net intraluminal appearance rate of AspPhe at 36% of the disappearance rate of APM. During steady-state PME perfusion, PHE had a significantly greater net appearance rate than during APM perfusion. Methanol appearance rates were slightly, but not significantly, higher during PME than during APM perfusions. The data suggest that (1) APM is hydrolyzed to AspPhe and both APM and PME are hydrolyzed to their constituent amino acids and and methanol prior to entering the portal circulation; (2) AspPhe is an important intraluminal intermediate in aspartame metabolism; and (3) aspartate is rapidly metabolized by the enterocyte.
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Ranney RE, Oppermann JA, Muldoon E, McMahon FG.
Comparative metabolism of aspartame in experimental animals and humans. Toxicol Environ Health. 1976 Nov;2(2):441-51.
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.
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Stegink LD, Filer LJ Jr, Bell EF, Ziegler EE, Tephly TR.
Effect of repeated ingestion of aspartame-sweetened beverage on plasma amino acid, blood methanol, and blood formate concentrations in normal adults. Metabolism. 1989 Apr;38(4):357-63.
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.
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Stegink LD.
The aspartame story: a model for the clinical testing of a food additive. Am J Clin Nutr. 1987 Jul;46(1 Suppl):204-15.
Toxicology is based on the premise that all compounds are toxic at some dose. Thus, it is not surprising that very large doses of aspartame (or its components--aspartate, phenylalanine, and methanol) produce deleterious effects in sensitive animal species. The critical question is whether aspartame ingestion is potentially harmful to humans at normal use and potential abuse levels. This paper reviews clinical studies testing the effects of various doses of aspartame upon blood levels of aspartate, phenylalanine, and methanol. These studies demonstrate that blood levels of these compounds are well below levels associated with adverse effects in sensitive animal species.
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Stegink LD, Brummel MC, McMartin K, Martin-Amat G, Filer LJ Jr, Baker GL, Tephly TR.
Blood methanol concentrations in normal adult subjects administered abuse doses of aspartame. J Toxicol Environ Health. 1981 Feb;7(2):281-90.
Blood methanol concentrations were measured in 30 normal adult subjects administered aspartame, a dipeptide methyl ester. The doses studied included the 99th percentile of projected daily ingestion (34 mg/kg body weight) and three doses considered to be in the abuse range (100, 150, and 200 mg/kg body weight). Methanol concentrations were below the level of detection (0.4 mg/dl) in the blood of the 12 normal subjects who ingested aspartame at 34 mg/kg. They were significantly elevated (p less than or equal to 0 .001) after ingestion of each abuse dose, with the mean peak blood methanol concentrations and the areas under the blood methanol concentration-time curve increasing in proportion to dose. Mean (+/- SD) peak blood methanol concentrations were 1.27 +/- 0.48 mg/dl at the 100 mg/kg dose, 2.14 +/- 0.35 mg/dl at the 150 mg/kg dose, and 2.58 +/- 0.78 mg/dl at the 200 mg/kg dose. Blood methanol concentrations returned to predosing levels by 8 h after administration of the 100 mg/kg dose. Methanol was still detected in the blood 8 h after the subjects had ingested aspartame at 150 or 200 mg/kg. Blood formate analyses were carried out in the 6 subjects who ingested aspartame at 200 mg/kg, since recent studies indicate that the toxic effects of methanol are due to formate accumulation. No significant increase in blood formate concentrations over predosing concentrations was noted. No changes were noted in any of the blood chemistry profile parameters measured 24 h after aspartame ingestion, compared to values noted before administration. Similarly, no differences were noted in ophthalmologic examinations carried out before and after aspartame loading.
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Stegink LD, Brummel MC, Filer LJ Jr, Baker GL.
Blood methanol concentrations in one-year-old infants administered graded doses of aspartame. J Nutr. 1983 Aug;113(8):1600-6.
Blood methanol concentrations were measured in 24 1-year-old infants administered aspartame, a dipeptide methyl ester sweetener. The doses studied included a dose projected to be the 99th percentile of daily ingestion for adults (34 mg/kg body weight), a very high use dose (50 mg/kg body weight) and a dose considered to be in the abuse range (100 mg/kg body weight). Blood methanol values in infants were compared to values observed previously in adults administered equivalent doses of aspartame. Methanol concentrations were below the level of detection (0.35 mg/dl) in the blood of 10 infants administered aspartame at 34 mg/kg body weight, but were significantly elevated (P less than or equal to 0.05) after ingestion of aspartame at 50 and 100 mg/kg body weight. At the latter doses, mean peak blood methanol concentrations and the area under the blood methanol concentration-time curve increased in proportion to dose. Mean (+/- SEM) peak blood methanol concentration was 0.30 +/- 0.10 mg/100 ml at a 50 mg/kg body weight aspartame dose (n = 6) and 1.02 +/- 0.28 mg/ml at the 100 mg/kg body weight dose (n = 8). Blood methanol values in infants were similar to those observed in normal adults.
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Filer LJ Jr, Stegink LD.
Aspartame metabolism in normal adults, phenylketonuric heterozygotes, and diabetic subjects. Diabetes Care. 1989 Jan;12(1):67-74.
This study reviews clinical studies testing the effects of various doses of aspartame on blood levels of phenylalanine, aspartate, and methanol in normal subjects and known phenylketonuric heterozygotes. The effect of aspartame on the phenylalanine-to-large neutral amino acid ratio under various feeding situations is shown. The clinical studies of aspartame in diabetic subjects are limited to observations of its effects on blood levels of glucose, lipids, insulin, and glucagon. These studies clearly demonstrate the safety of this high-intensity sweetener for use by humans.
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