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Aspartame is an artificial sweetener par excellence, in terms of its world market share, coupled with 26 years of intractable, polarized controversy about its safety, since its approval by the USA FDA for dry foods in July, 1981, and then for beverages in July, 1983.
''Article temporarily moved to [[Aspartame/Draft]] pending revisioning.''
 
As a dipeptide, its molecule is made of two normal, essential amino acids, phenylalanine (50 % by weight) and aspartic acid, (39 %), loosely bound together by a smaller methyl unit (11 %).
 
At temperatures above body heat, and at low levels of acidity (PH), and soon after ingestion, it readily splits and releases its three components, which follow largely independent paths in humans.
 
Each molecule of aspartame releases one molecule of each of the three parts.
 
The methyl unit becomes methanol, better known as wood alcohol, CH3OH, which is uaually an impurity in alcohol beverages, especially dark wines and liquors, at a level above 100 mg/l, one part in 10,000 by weight.
 
Methanol itself is not very toxic.  Its harm results from the production of formaldehyde and formic acid.
 
An enzyme, alcohol dehydrogenase, converts most methanol in blood into formaldehyde, a toxin, and much of the formaldehyde is soon made into formic acid, another toxin, and much of that eliminated as water and carbon dioxide.
 
However, the enzyme first is tied up with any available ethanol, C2H5OH, turning it into acetaldehyde, also toxic, until, after all the available ethanol is gone, the enzyme then quickly turns any methanol into formaldehyde.
 
Two teams published research in 1987 and 2005, showing that methanol in alcohol beverages taken before bedtime, resulted in hangover symptoms in healthy young students as long as 13 hours later, when the ethyl alcohol was all gone, but the remaining methanol was rapidly becoming formaldehyde.
 
The aspartame content of two liters diet soda, 5.6 12-oz cans, is 1,120 mg, releasing 11 % as 123 mg methanol.
 
Usually, there is not a concurrent larger amount of ethanol taken, which would prevent the production of formaldehyde.
 
So, the methanol from any aspartame is quickly turned into formaldehyde.
 
An expert review by a competent, unbiased team led by M. Bouchard, 2001, cites references, many from aspartame industry funded studies, states that about 30 - 40 % of the methanol remains in the body as
unknown, durable reaction products.
 
J. Nutrition 1973 Oct; 103(10): 1454-1459.
Metabolism of aspartame in monkeys.
Oppermann JA, Muldoon E, Ranney RE.
Dept. of Biochemistry, Searle Laboratories,
Division of G.D. Searle and Co. Box 5110, Chicago, IL 60680
 
They found that about 70 % of the radioactive methanol in aspartame put into the stomachs of 3 to 7 kg monkeys was eliminated within 8 hours, with little additional elimination, as carbon dioxide in exhaled air and as water in the urine
 
They did not report any studies on the distribution of radioactivity in body tissues, except that blood plasma proteins after 4 days held 4 % of the initial methanol.
 
The low oral dose of aspartame and for methanol was 0.068 mmol/kg, about 1 part per million [ppm]
of the acute toxicity level of 2,000 mg/kg, 67,000 mmol/kg, used by McMartin (1979).
 
Two L daily use of diet soda provides 123 mg methanol, 2 mg/kg for a 60 kg person, a dose of 67 mmole/kg, a thousand times more than the dose in this study.
 
By eight hours excretion of the dose in air and urine had leveled off at 67.1 +-2.1 % as CO2 in the exhaled air and 1.57+-0.32 % in the urine, so 68.7 % was excreted, and 31.3 % was retained.
 
This data is the average of 4 monkeys.  "...the 14C in the feces was negligible."
 
"That fraction not so excreted (about 31%) was converted to body constituents through the one-carbon metabolic pool."  "All radioactivity measurements were counted to +-1 % accuracy..."
 
The abstract ends, "It was concluded that aspartame was digested to its three constituents that were then absorbed as natural constituents of the diet."
 
 
 
http://health.groups.yahoo.com/group/aspartameNM/message/1143
 
http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169
 
 
"Exposure to methanol also results from the consumption of certain foodstuffs (fruits, fruit juices, certain vegetables, aspartame sweetener, roasted coffee, honey) and alcoholic beverages (Health Effects Institute, 1987; Jacobsen et al., 1988)."
 
"Experimental studies on the detailed time profiles following controlled repeated exposures to methanol are lacking."
 
"Thus, in monkeys and plausibly humans, a much larger fraction of body formaldehyde is rapidly converted to unobserved forms rather than passed on to formate and eventually CO2."
 
"However, the volume of distribution of formate was larger than that of methanol, which strongly suggests that formate distributes in body constituents other than water, such as proteins."
 
http://groups.yahoo.com/group/aspartameNM/message/1143
 
methanol (formaldehyde, formic acid) disposition: Bouchard M et al, full plain text, 2001: substantial sources are degradation of fruit pectins, liquors, aspartame, smoke: Murray 2005.04.02
http://www.toxsci.oupjournals.org/cgi/content/full/64/2/169
Toxicological Sciences 64, 169-184 (2001)
Copyright © 2001 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETIC
A Biologically Based Dynamic Model for Predicting the Disposition of Methanol and Its Metabolites in Animals and Humans
 
Michèle Bouchard *, ^,1,  [email protected]
 
Robert C. Brunet, ^^  [email protected]
 
Pierre-Olivier Droz, ^
 
and Gaétan Carrier *  [email protected]
 
* Department of Environmental and Occupational Health, Faculty of Medicine,
Université de Montréal, P.O. Box 6128, Main Station, Montréal, Québec,
Canada, H3C 3J7;
 
^ Institut Universitaire romand de Santé au Travail, rue du Bugnon 19,
CH-1005, Lausanne, Switzerland, and
 
^^  Département de Mathématiques et de Statistique and Centre de Recherches
Mathématiques, Faculté des arts et des sciences, Université de Montréal,
P.O. Box 6128, Main Station, Montréal, Québec, Canada, H3C 3J7
 
1 To whom correspondence should be addressed at Département de santé
environnementale et santé au travail, Université de Montréal, P.O. Box 6128,
Main Station, Montréal, Québec, H3C 3J7, Canada. Fax: (514) 343-2200.
 
Received May 10, 2001; accepted August 28, 2001
 
ABSTRACT
A multicompartment biologically based dynamic model was developed to describe the time evolution of methanol and its metabolites in the whole body and in accessible biological matrices of rats, monkeys, and humans following different exposure scenarios.
 
The dynamic of intercompartment exchanges was described mathematically by a mass balance differential equation system.
 
The model's conceptual and functional representation was the same for rats, monkeys, and humans, but relevant published data specific to the species of interest served to determine the critical parameters of the kinetics.
 
Simulations provided a close approximation to kinetic data available in the published literature.
The average pulmonary absorption fraction of methanol was estimated to be 0.60 in rats, 0.69 in monkeys, and 0.58-0.82 in human volunteers.
 
The corresponding average elimination half-life of absorbed methanol through metabolism to formaldehyde was estimated to be 1.3, 0.7-3.2, and 1.7 h.
 
Saturation of methanol metabolism appeared to occur at a lower exposure in rats than in monkeys and humans.
 
Also, the main species difference in the kinetics was attributed to a metabolism rate constant of whole body formaldehyde to formate estimated to be twice as high in rats as in monkeys.
 
Inversely, in monkeys and in humans, a larger fraction of body burden of formaldehyde is rapidly transferred to a long-term component.
 
The latter represents the formaldehyde that (directly or after oxidation to formate) binds to various endogenous molecules or is taken up by the tetrahydrofolic-acid-dependent one-carbon pathway to become the building block of synthetic pathways.
 
This model can be used to quantitatively relate methanol or its metabolites in biological matrices to the absorbed dose and tissue burden at any point in time in rats, monkeys, and humans for different exposures, thus reducing uncertainties in the dose-response relationship, and animal-to-human and
exposure scenario comparisons.
 
The model, adapted to kinetic data in human volunteers exposed acutely to methanol vapors, predicts that 8-h inhalation exposures ranging from 500 to 2000 ppm, without physical activities, are needed to increase concentrations of blood formate and urinary formic acid above mean background values
reported by various authors (4.9-10.3 and 6.3-13 mg/liter, respectively).
 
This leaves blood and urinary methanol concentrations as the most sensitive biomarkers of absorbed methanol.
 
Key Words: methanol; formaldehyde; formate; toxicokinetics; modeling; animals; humans.
 
"However, the severe toxic effects are usually associated with the production and accumulation of formic acid, which causes metabolic acidosis and visual impairment that can lead to blindness and death at blood concentrations of methanol above 31 mmol/l (Røe, 1982; Tephly and McMartin, 1984; U.S. DHHS, 1993).
 
Although the acute toxic effects of methanol in humans are well documented, little is known about the chronic effects of low exposure doses, which are of interest in view of the potential use of methanol as an engine fuel and current use as a solvent and chemical intermediate.
 
Gestational exposure studies in pregnant rodents (mice and rats) have also shown that high methanol inhalation exposures (5000 or 10,000 ppm and more, 7 h/day during days 6 or 7 to 15 of gestation) can induce birth defects (Bolon et al., 1993; IPCS, 1997; Nelson et al., 1985)."
 
"The corresponding average elimination half-life of absorbed methanol through metabolism to formaldehyde was estimated to be 1.3, 0.7-3.2, and 1.7 h."
 
"Inversely, in monkeys and in humans, a larger fraction of body burden of formaldehyde is rapidly transferred to a long-term component.
 
The latter represents the formaldehyde that (directly or after oxidation to formate) binds to various endogenous molecules..."
 
"Animal studies have reported that systemic methanol is eliminated mainly by metabolism (70 to 97% of absorbed dose) and only a small fraction is eliminated as unchanged methanol in urine and in the expired air (< 3-4%) (Dorman et al., 1994; Horton et al., 1992).
 
Systemic methanol is extensively metabolized by liver alcohol dehydrogenase and catalase-peroxidase enzymes to formaldehyde, which is in turn rapidly oxidized to formic acid by formaldehyde dehydrogenase enzymes (Goodman and Tephly, 1968; Heck et al., 1983; Røe, 1982; Tephly and McMartin, 1984).
 
Under physiological conditions, formic acid dissociates to formate and hydrogen ions.
 
Current evidence indicates that, in rodents, methanol is converted mainly by the catalase-peroxidase system whereas monkeys and humans metabolize methanol mainly through the alcohol dehydrogenase system (Goodman and Tephly, 1968; Tephly and McMartin, 1984).
 
Formaldehyde, as it is highly reactive, forms relatively stable adducts with cellular constituents (Heck et al., 1983; Røe, 1982)."
 
"The whole body loads of methanol, formaldehyde, formate, and unobserved by-products of formaldehyde metabolism were followed.
 
Since methanol distributes quite evenly in the total body water, detailed compartmental representation of body tissue loads was not deemed necessary."
 
"According to model predictions, congruent with the data in the literature (Dorman et al., 1994; Horton et al., 1992), a certain fraction of formaldehyde is readily oxidized to formate, a major fraction of which is rapidly converted to CO2 and exhaled, whereas a small fraction is excreted as formic acid in urine.
 
However, fits to the available data in rats and monkeys of Horton et al. (1992) and Dorman et al. (1994) show that, once formed, a substantial fraction of formaldehyde is converted to unobserved forms.
 
This pathway contributes to a long-term unobserved compartment.
 
The latter, most plausibly, represents either the formaldehyde that (directly or after oxidation to formate) binds to various endogenous  molecules (Heck et al., 1983; Røe, 1982) or is incorporated in the tetrahydrofolic-acid-dependent one-carbon pathway to become the building block of a number of synthetic pathways (Røe, 1982; Tephly and McMartin, 1984).
 
That substantial amounts of methanol metabolites or by-products are retained for a long time is verified by Horton et al. (1992) who estimated that 18 h following an iv injection of 100 mg/kg of 14C-methanol in male Fischer-344 rats, only 57% of the dose was eliminated from the body.
 
From the data of Dorman et al. (1994) and Medinsky et al. (1997), it can further be calculated that 48 h following the start of a 2-h inhalation exposure to 900 ppm of 14C-methanol vapors in female cynomolgus monkeys, only 23 % of the absorbed 14C-methanol was eliminated from the body.
 
These findings are corroborated by the data of Heck et al. (1983) showing that 40 % of a 14C-formaldehyde inhalation dose remained in the body 70 h postexposure.
 
In the present study, the model proposed rests on acute exposure data, where the time profiles of methanol and its metabolites were determined only over short time periods (a maximum of 6 h of exposure and a maximum of 48 h postexposure).
 
This does not allow observation of the slow release from the long-term components.
 
It is to be noted that most of the published studies on the detailed disposition kinetics of methanol regard controlled short-term (iv injection or continuous inhalation exposure over a few hours) methanol exposures in rats, primates, and humans (Batterman et al., 1998; Damian and Raabe, 1996;
Dorman et al., 1994; Ferry et al., 1980; Fisher et al., 2000; Franzblau et al., 1995; Horton et al., 1992; Jacobsen et al., 1988; Osterloh et al., 1996; Pollack et al., 1993; Sedivec et al., 1981; Ward et al., 1995; Ward and Pollack, 1996).
 
Experimental studies on the detailed time profiles following controlled repeated exposures to methanol are lacking."
 
"Thus, in monkeys and plausibly humans, a much larger fraction of body formaldehyde is rapidly converted to unobserved forms rather than passed on to formate and eventually CO2."
 
"However, the volume of distribution of formate was larger than that of methanol, which strongly suggests that formate distributes in body constituents other than water, such as proteins.
 
The closeness of our simulations to the available experimental data on the time course of formate blood concentrations is consistent with the volume of distribution concept (i.e., rapid exchanges between the nonblood pool of formate and blood formate)."
 
"Also, background concentrations of formate are subject to wide interindividual variations (Baumann and Angerer, 1979; D'Alessandro et al., 1994; Franzblau et al., 1995; Heinrich and Angerer, 1982; Lee et al., 1992; Osterloh et al., 1996; Sedivec et al., 1981)."
 
 
 
http://groups.yahoo.com/group/aspartameNM/message/1286
 
methanol products (formaldehyde and formic acid) are main cause of alcohol hangover symptoms [same as from similar amounts of methanol, the 11% part of aspartame]: YS Woo et al, 2005 Dec: Murray 2006.01.20
 
Addict Biol. 2005 Dec;10(4): 351-5.
Concentration changes of methanol in blood samples during an experimentally induced alcohol hangover state.
Woo YS, Yoon SJ, Lee HK, Lee CU, Chae JH, Lee CT, Kim DJ.
Chuncheon National Hospital, Department of Psychiatry, The Catholic University of Korea, Seoul, Korea. [ Han-Kyu Lee ]
 
A hangover is characterized by the unpleasant physical and mental symptoms that occur between 8 and 16 hours after drinking alcohol.
 
After inducing experimental hangover in normal individuals, we measured the methanol concentration prior to and after alcohol consumption and we assessed the association between the hangover condition
and the blood methanol level.
 
A total of 18 normal adult males participated in this study.
 
They did not have any previous histories of psychiatric or medical disorders.
 
The blood ethanol concentration prior to the alcohol intake (2.26+/-2.08) was not significantly different from that 13 hours after the alcohol consumption (3.12+/-2.38).
 
However, the difference of methanol concentration between the day of experiment (prior to the alcohol intake) and the next day (13 hours after the alcohol intake) was significant (2.62+/-1.33/l vs. 3.88+/-2.10/l, respectively).
 
[ So, the normal methanol level was 2.62 mg per liter, and increasing that by 50% = 1.3 mg per liter to 3.88 mg per liter caused hangover symptoms.
 
The human body has about 5.6 liters blood, so adding 1.3 mg per liter gives an estimate of 7.3 mg added methanol, as much as 4 oz diet soda.
 
Diet soda is about 200 mg aspartame per 12 oz can, which is 22 mg (11% methanol), 1.83 mg methanol per ounce.
 
Also, this 50 % increase in blood methanol that caused roughly similar symptoms in South Koreans, Woo YS, 2005, as in men in Swedem who had a 6-fold increase in urine methanol, confirms many studies that show that specific genetic differences make Asians and American Indians much more vulnerable to inebriation, hangover, and addiction than Europeans. Bendtsen P, Jones AW, Helander A. 1998 ]
 
A significant positive correlation was observed between the changes of blood methanol concentration
and hangover subjective scale score increment when covarying for the changes of blood ethanol level (r=0.498, p<0.05).
 
This result suggests the possible correlation of methanol as well as its toxic metabolite to hangover. PMID: 16318957
 
[ The "toxic metabolite" of methanol is formaldehyde, which in turn
partially becomes formic acid -- both potent cumulative toxins
that are the actual cause of the toxicity of methanol.]
 
 
Int J Neurosci. 2003 Apr; 113(4): 581-94.
The effects of alcohol hangover on cognitive functions in healthy subjects.
Kim DJ, Yoon SJ, Lee HP, Choi BM, Go HJ.
Department of Psychiatry, College of Medicine, Catholic University of Korea, Buchon City, Kyunggi Do, Korea.
 
A hangover is characterized by the constellation of unpleasant physical and mental symptoms that occur between 8 and 16 h after drinking alcohol.
 
We evaluated the effects of experimentally-induced alcohol hangover on cognitive functions using the Luria-Nebraska Neuropsychological Battery.
 
A total of 13 normal adult males participated in this study.
 
They did not have any previous histories of psychiatric or medical disorders.
 
We defined the experimentally-induced hangover condition at 13 h after drinking a high dose of alcohol (1.5 g/kg of body weight).
 
We evaluated the changes of cognitive functions before drinking alcohol and during experimentally-induced hangover state.
 
The Luria-Nebraska Neuropsychological Battery was administrated in order to examine the changes of cognitive functions.
 
Cognitive functions, such as visual, memory, and intellectual process functions, were decreased during the hangover state.
 
Among summary scales, the profile elevation scale was also increased.
 
Among localization scales, the scores of left frontal, sensorimotor, parietal-occipital dysfunction, and right parietal-occipital scales were increased during the hangover state.
 
These results indicate that alcohol hangovers have a negative effect on cognitive functions, particularly on the higher cortical and visual functions associated with the left hemisphere and right posterior hemisphere.  Publication Types: Clinical Trial PMID: 12856484
 
 
 
Alcohol Alcohol. 1998 Jul-Aug; 33(4): 431-8.
Urinary excretion of methanol and 5-hydroxytryptophol as biochemical markers of recent drinking in the hangover state. [email protected]
Bendtsen P, Jones AW, Helander A. [email protected]
Drug Dependence Unit, University Hospital, Linkoping, Sweden.
 
Twenty healthy social drinkers (9 women and 11 men) drank either 50 g of ethanol (mean intake 0.75 g/kg) or 80 g (mean 1.07 g/kg) according to choice as white wine or export beer in the evening over 2 h with a meal.
 
After the end of drinking, at bedtime, in the following morning after waking-up, and on two further occasions during the morning and early afternoon, breath-alcohol tests were performed and samples of urine were collected for analysis of ethanol and methanol and the 5-hydroxytryptophol (5-HTOL) to 5-hydroxyindol-3-ylacetic acid (5-HIAA) ratio.
 
The participants were also asked to quantify the intensity of hangover symptoms (headache, nausea, anxiety, drowsiness, fatigue, muscle aches, vertigo) on a scale from 0 (no symptoms) to 5 (severe symptoms).
 
The first morning urine void collected 6-11 h after bedtime as a rule contained measurable amounts of ethanol, being 0.09 +/- 0.03 g/l (mean +/- SD) after 50 g and 0.38 +/- 0.1 g/l after 80 g ethanol.
 
The corresponding breath-alcohol concentrations were zero, except for three individuals who registered 0.01-0.09g/l.
 
Ethanol was not measurable in urine samples collected later in the morning and early afternoon.
 
The peak urinary methanol occurred in the first morning void, when the mean concentration after 80 g ethanol was approximately 6-fold higher than pre-drinking values.
 
[ This is a much greater increase of methanol than the 50 % increase that cause roughly similar symptoms in South Koreans, Woo YS, 2005, confirming many studies that show that specific genetic differences make Asians and American Indians much more vulnerable to inebriation, hangover, and addiction. ]
 
This compares with a approximately 50-fold increase for the 5-HTOL/5-HIAA ratio in the first morning void.
 
Both methanol and the 5-HTOL/5-HIAA ratio remained elevated above pre-drinking baseline values in the second and sometimes even the third morning voids.
 
Most subjects experienced only mild hangover symptoms after drinking 50 g ethanol (mean score 2.4 +/- 2.6), but the scores were significantly higher after drinking 80 g (7.8 +/- 7.1).
 
The most common symptoms were headache, drowsiness, and fatigue.
 
A highly significant correlation (r = 0.62-0.75, P <0.01) was found between the presence of headache, nausea, and vertigo and the urinary methanol concentration in the first and second morning voids, whereas 5-HTOL/5-HIAA correlated with headache and nausea.
 
These results show that analysing urinary methanol and 5-HTOL furnishes a way to disclose recent drinking after alcohol has no longer been measurable by conventional breath-alcohol tests for at least 5-10 h.
 
The results also support the notion that methanol may be an important factor in the aetiology of hangover. PMID: 9719404
 
 
 
http://groups.yahoo.com/group/aspartameNM/message/1373
 
aspartame rat brain toxicity re cytochrome P450 enzymes, expecially CYP2E1, Vences-Mejia A, Espinosa-Aguirre JJ et al, 2006 Aug, Hum Exp Toxicol: relevant abstracts re formaldehyde from methanol in alcohol drinks: Murray 2006.09.29
 
[ Rich Murray notes:
As a medical layman, noting that all readers are laymen for any topic outside the bounds of their specific expertise, I found related abstracts that illucidate the role of cytochrome P450 enzymes, especially the one most affected by aspartame, CYP2E1, in brain toxicity processes involving ethanol and methanol, suggesting avenues of research for alcohol addiction and hangover, and the possibilies of aspartame liver and brain toxicity from its 11 % methanol component. ]
 
"A major finding in this study was that the daily consumption of ASP at the two doses considered leads to an increment in the concentration and activity of CYP2B1/2, CYP2E1 and CYP3A2 in rat cerebral and cerebellar microsomes....
 
The highest increment (up to 25-fold over controls) in a CYP-associated activity induced by ASP in brain was that of 4-NPH corresponding to CYP2E1.
 
The results mentioned above must be reproduced using a broad range of ASP concentrations in order to define the existence of a dose-related effect.
 
As far as we know, this is the first report regarding modulation of brain CYPs by the widely used
sweetener ASP.
 
Specific induction of brain CYPs could constitute a local regulatory mechanism of enzyme activity, thus influencing drug response;
for tissues exhibiting low regenerative capacity, such as the brain, such modulation would probably be of major toxicological significance....
 
It has already been said that once ASP enters the organism, it is rapidly metabolized by intestinal
esterases and dipeptidases to aspartic acid, phenylalanine and methanol, substances normally found in the diet and body. 37
 
One hour after ASP intake at a dose of 200 mg/kg body weight by rats, corresponding to the acceptable FDA daily intake for the sweetener after species correction, increased plasma and brain phenylalanine levels by 62 % and 192 % respectively. 6
 
With regard to methanol, it accounts for about 10 % of the ASP weight administered. 38
 
We can hypothesize that the exposure to methanol at the two regimens used in this study ( about 7.5 and 12.5 mg/kg from the doses of 75 and 125 mg/kg ) could induce xenobiotic-metabolizing enzymes in a
similar way to that of the chronic administration of ethanol. 39....
 
If methanol is the metabolite responsible for the induction of brain CYP2E1 seen in this work, the question of why the hepatic CYP2E1 was not altered remains.
 
Experiments with the three metabolites resulting from ASP metabolism are currently being undertaken in our laboratory in order to address this question.
 
In conclusion, data obtained demonstrated that a daily consumption of ASP at doses of 75 and 125 mg/kg body weight over 30 days provokes a substantial increment in CYP enzymes involved in endogenous and exogenous molecules metabolism in the CNS of the rat.
 
Biological consequences of this phenomenon should be investigated in view of the high number of humans exposed to this artificial sweetener and because of the recent data indicating the potential carcinogenic effects of this compound. 41"
 
"The aim of this study was to explore the effect of orally ingested ASP upon the expression and activity of CYP families involved in the CNS of rats.
 
The chosen ASP doses of 75 and 125 mg/kg body weight used in this study are within the limits of
human consumption after species factor correction.
 
Because rats metabolize ASP faster than humans, 31 dose comparisons between them have usually been
corrected by a factor of 5.
 
After correction, doses used here are below the FDA (50 mg/kg body weight) and Health and Welfare Canada (40 mg/kg body weight) acceptable daily intake for ASP. 32,33"
 
 
Hum Exp Toxicol. 2006 Aug; 25(8): 453-9.
The effect of aspartame on rat brain xenobiotic-metabolizing enzymes.
 
Vences-Mejia A 1,
 
Labra-Ruiz N 1,
 
Hernandez-Martinez N 1,
 
Dorado-Gonzalez V 1,
 
Gomez-Garduno J 1,
 
Perez-Lopez I 1,
 
Nosti-Palacios R 1,
 
Camacho Carranza R 2,
 
Espinosa-Aguirre JJ 2.
 
Laboratorio de Toxicologia Genetica,
 
1: Instituto Nacional de Pediatria, Insurgentes Sur, 3700-C, 04530 Mexico, DF Mexico.
 
2: Instituto de Investigaciones Biomédicas, UNAM, Apartado postal 70228, Ciudad Universitaria 04510 México, D.F., México
 
http://www.biomedicas.unam.mx/index.asp
 
*Correspondence: JJ Espinosa-Aguirre, Instituto de Investigaciones Biome´dicas, UNAM, Apartado postal 70228, Ciudad Universitaria 04510 Me´xico, D.F., Me´xico
 
Human & Experimental Toxicology (2006) 25(8): 453-459.
 
www.sagepublications.com c 2006 SAGE Publications 10.1191/0960327106het646oa
 
[ Dra. Araceli Vences M
 
Jefa de Laboratorio de Toxicologia Genetica, 6° P de Hospital Laboratorios, 10 84 09 00 Ext.1410 -1448  [email protected]
 
ISRAEL PÉREZ LÓPEZ,
 
JAVIER J. ESPINOSA AGUIRRE, [email protected]
 
http://www.biomedicas.unam.mx/investigacionFrame.asp?ID=MG ]
 
Abstract
 
This study demonstrates that chronic aspartame (ASP) consumption leads to an increase of phase I metabolizing enzymes (cytochrome P450 (CYP)) in rat brain.
 
Wistar rats were treated by gavage with ASP at daily doses of 75 and 125 mg/kg body weight for 30 days.
 
Cerebrum and cerebellum were used to obtain microsomal fractions to analyse activity and protein levels of seven cytochrome P450 enzymes.
 
Increases in activity were consistently found with the 75 mg/kg dose both in cerebrum and cerebellum for all seven enzymes, although not at the same levels:
 
CYP2E1-associated 4-nitrophenol hydroxylase (4-NPH) activity was increased 1.5-fold in cerebrum and 25-fold in cerebellum;
 
likewise, CYP2B1-associated penthoxyresorufin O-dealkylase (PROD) activity increased 2.9- and 1.7-fold respectively,
 
CYP2B2-associated benzyloxyresorufin O-dealkylase (BROD) 4.5- and 1.1-fold,
 
CYP3A-associated erythromycin N-demethylase (END) 1.4- and 3.3-fold,
 
CYP1A1-associated ethoxyresorufin O-deethylase (EROD) 5.5- and 2.8-fold,
 
and CYP1A2-associated methoxyresorufin O-demethylase (MROD) 3.7- and 1.3-fold.
 
Furthermore, the pattern of induction of CYP immunoreactive proteins by ASP paralleled that of 4-NHP-, PROD-, BROD-, END-, EROD- and MROD-related activities only in the cerebellum.
 
Conversely, no differences in CYP concentration and activity were detected in hepatic microsomes of treated animals with respect to the controls, suggesting a brain-specific response to ASP treatment.
PMID: 16937917 Aug 14 2006 08:07:58
 
Key words: aspartame; brain; cytochrome P450; enzyme induction
 
Introduction
 
Sweeteners are paid special attention among food additives, as their use enables a sharp reduction in sugar consumption and a significant decrease in caloric intake while maintaining the desirable palatability of foods and soft drinks.
 
Sweeteners are also of primary importance as part of nutritional guidance for diabetes, a disease with increasing incidence in developed countries. 1-3
 
Aspartame (L-asparthyl-L-phenylalanine methyl ester, ASP) is one of the most widely used artificial sweeteners; it is a high-intensity sweetener added to a large variety of foods, most commonly found in
low-calorie beverages, desserts and tabletop sweeteners added to tea or coffee.
 
It does not enter into the bloodstream intact, but is hydrolyzed in the intestine to form aspartate,
phenylalanine and methanol, which are then absorbed into the circulation, elevating their levels in plasma and in brain phenylalanine and tyrosine levels as well. 4-6
 
Aspartate is a highly excitatory neurotransmitter 7 and phenylalanine is a precursor of catecholamines in the brain; 8 increased levels of these molecules could change the basic activity level of the brain to an unhealthy, constantly stimulated state.
 
Short-term studies on ASP consumption and memory loss have been conducted in humans and rodents and no relationship was found. 9-11
 
On the other hand, chronic studies have implicated ASP consumption in learning and memory.
 
Consumption of 9% ASP in the diet for 13 weeks affected learning behaviour in male rats, 12 while ASP exposure of guinea pigs to 500 mg/kg during gestation disrupted odour-associative learning in pups. 13
 
Recently, Christian et al. reported that chronic ASP consumption lengthened the time it took rats to find the reward in a T-maze and increased the number of muscarinic receptors in specific brain areas. 14
 
[ 12 Potts WJ, Bloss JL, Nutting EF. Biological properties of aspartame:
I. Evaluation of central nervous system effects. J Environ Pathol Toxicol 1980; 3: 341=353.�
 
13 Dow-Edwards DL, Scribani LA, Riley EP.
Impaired performance on odor-aversion testing following prenatal aspartame exposure in the guinea pig.
Neurotoxicol Teratol 1989; 11: 413-416.
 
14 Christian B, McConnaughey K, Bethea E, Brantley S, Coffey A, Hammond L, et al.
Chronic aspartame affects T-maze performance, brain cholinergic receptors and Na�, K�-ATPase in rats. P
Pharmacol Biochem Behav 2004; 78: 121-127. ]
 
 
Despite numerous toxicological studies of ASP and its components, its effects on metabolic and detoxification enzyme systems have received little attention.
 
Metabolic enzymes are of special interest as changes in their function could lead to an increased susceptibility of the organisms to the harmful effects of a variety of contaminants found in the environment and in food products. 15,16
 
The presence of cytochrome P450 (CYP) in the central nervous system (CNS) opens the question of
whether metabolism in endothelial cells may regulate the penetration of the xenobiotics into the
brain compartment. 17,18
 
The role of CYP in brain includes such diverse functions as aromatization of androgens to oestrogens,
formation of catechols, and it may also participate in the metabolism of neurotransmitters and of xenobiotics. 17,19
 
Moreover, lipophilic xenobiotics can diffuse through the endothelial cells of the brain capillaries
and enter the neuronal cells.
 
Thus, in situ activation in the neuronal cell could have far-reaching consequences by causing irreversible disruption of the neuronal function.
 
The brain is the target not only for a number of toxic compounds but also for several psychoactive drugs.
 
The metabolism of drugs in the brain can lead to local pharmacological modulation at the site of action and can result in variable drug response. 17
 
The purpose of this work is to study the effect of orally administered ASP on the activity of CYP in
the CNS of the rat.
 
The characterization of brain specific CYP and its regulation and localization within the CNS is gaining importance for the understanding of the potential role of these enzymes in the pathogenesis of neurodegenerative disorders and in the psychopharmacological modulation of drugs acting on the CNS. 17
 
 
 
 
Free Radic Res. 1997 Oct; 27(4): 369-75.
Decreased antioxidant defense mechanisms in rat liver after methanol
intoxication.
 
Skrzydlewska E,
 
Farbiszewski R.
 
Department of Instrumental Analysis, Medical Academy, Poland.
 
The primary metabolic fate of methanol is oxidation to formaldehyde and then to formate by enzymes of the liver.
 
Cytochrome P-450 and a role for the hydroxyl radical have been implicated in this process.
 
The aim of the paper was to study the liver antioxidant defense system in methanol intoxication, in doses of 1.5, 3.0 and 6.0 g/kg b.w., after methanol administration to rats.
 
In liver homogenates, the activities of Cu,Zn-superoxide dismutase and catalase were significantly increased after 6 h following methanol ingestion in doses of 3.0 and 6.0 g/kg b.w. and persisted up to 2-5 days, accompanied by significant decrease of glutathione reductase and glutathione peroxidase activities.
 
The content of GSH was significantly decreased during 6 hours to 5 days.
 
The liver ascorbate level was significantly diminished, too, while MDA levels were considerably increased after 1.5, 3.0 and 6.0 g/kg b.w. methanol intoxication.
 
Changes due to methanol ingestion may indicate impaired antioxidant defense mechanisms in the liver tissue.  PMID: 9416465
 
 
 
Wien Klin Wochenschr. 1988 Apr 29; 100(9): 282-8.
[Methanol--an up-to-now neglected constituent of all alcoholic beverages. A new biochemical approach to the problem of chronic alcoholism] [Article in German]
 
Sprung R,
 
Bonte W,
 
Lesch OM.
 
Institut fur Rechtsmedizin, Universitat Gottingen.
 
Alcoholism is usually understood as ethanolism.
 
There is some evidence that its oxidation product acetaldehyde may condense with endogenous amines to form tetrahydroisoquinoline (TIQ) and - tetrahydro-beta-carboline (THBC) alkaloids which ultimately might be responsible for addiction.
 
In most animal experiments pure ethanol solutions were fed, but chronic alcoholics prefer normal alcoholic beverages, and it is widely ignored that all these beverages without exception also
contain methanol.
 
Its metabolite formaldehyde is a much more potent reaction partner for TIQ and THBC formation than
acetaldehyde.
 
As our findings in chronic alcoholics proved that these persons in contrast to healthy subjects are able to oxidize methanol despite high ethanol levels, there must be a continuous leakage of formaldehyde.
 
And it seems possible that methanol plays a more significant role in the pathophysiology and possibly the etiology of chronic alcoholism than ethanol.  PMID: 3291400
 
 
 
Wien Klin Wochenschr. 1991; 103(22): 684-9.
 
[Methanol metabolism in chronic alcoholism] [Article in German]
 
Soyka M,
 
Gilg T,
 
von Meyer L,
 
Ora I.
 
Psychiatrische Klinik, Universitat Munchen.
 
Serum methanol concentrations (SMC) exceeding 10 mg/l are highly suggestive of long-term alcohol intoxication and can be considered as marker for chronic alcohol abuse.
 
Endogenously formed or consumed methanol is almost exclusively metabolized by alcohol dehydrogenase.
 
As long as blood alcohol concentrations exceed 0.2-0.5 g/l methanol cannot be metabolized and accumulates.
 
In a prospective study on 78 patients admitted for alcohol detoxification, elevated SMC up to 78 mg/l were found, with a mean SMC of 29.4 mg/l.
 
No correlation was demonstrated between SMC and severity of the alcohol withdrawal syndrome.
 
Further clinical, forensic and biochemical aspects of methanol metabolism are discussed. PMID: 1776249
 
 
http://en.wikipedia.org/wiki/Methanol  2007.11.22
 
Health and safety
 
Methanol is toxic by two mechanisms. Firstly, methanol (whether it enters the body by ingestion, inhalation, or absorption through the skin) can be fatal due to its CNS depressant properties in the same manner as ethanol poisoning.
 
Secondly, it is toxic by its breakdown (toxication) by the enzyme alcohol dehydrogenase in the liver by forming formic acid and formaldehyde which cause permanent blindness by destruction of the optic nerve.[2]
 
Fetal tissue will not tolerate methanol.
 
Dangerous doses will build up if a person is regularly exposed to vapors or handles liquid without skin protection.
 
If methanol has been ingested, a doctor should be contacted immediately.
 
The usual fatal dose is 100 – 125 mL or grams = 4 fl oz.
 
[ Aspartame is 11 % methanol.
 
A 12-oz can of diet soda has about 200 mg aspartame, which quickly releases 22 mg methanol into the body.
 
Two liters of diet soda, 5.6 12 oz cans, can quickly put 123 mg methanol into the body.
 
This is just one thousandth of a lethal dose -- however, given 200 million users, if 1/1000 is using 2  L daily, and 1/10 of those are, at a guess, 10 times more vulnerable, that leaves 20,000 who could be accumulating various toxic products, getting troublesome symptoms, reacting to a variety of drugs, having more accidents, diseases, and life stress, and perhaps developing hypersensitivity -- just the sort of stories that arrive every week from new members of [email protected], now 1,050 current members since Jan., 1999.  It's long overdue to do a thorough, competent study of these aspartame clients. ]
 
Toxic effects take hours to start, and effective antidotes can often prevent permanent damage.
 
This is treated using ethanol or fomepizole.[3]
 
Either of these drugs acts to slow down the action of alcohol dehydrogenase on methanol by means of competitive inhibition, so that it is excreted by the kidneys rather than being transformed into toxic metabolites.
 
The initial symptoms of methanol intoxication are those of central nervous system depression: headache, dizziness, nausea, lack of coordination, confusion, drowsiness, and with sufficiently large doses, unconsciousness and death.
 
The initial symptoms of methanol exposure are usually less severe than the symptoms resulting from the ingestion of a similar quantity of ethyl alcohol.
 
Once the initial symptoms have passed, a second set of symptoms arises 10–30 hours after the initial exposure to methanol: blurring or complete loss of vision, together with acidosis.
 
These symptoms result from the accumulation of toxic levels of formate in the bloodstream, and may progress to death by respiratory failure.

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