title: Chronic aspartame intake causes changes in the trans-sulphuration pathway, glutathione depletion and liver damage in mice.
abstract: No-caloric sweeteners, such as aspartame, are widely used in various food and beverages to prevent the increasing rates of obesity and diabetes mellitus, acting as tools in helping control caloric intake. Aspartame is metabolized to phenylalanine, aspartic acid, and methanol. Our aim was to study the effect of chronic administration of aspartame on glutathione redox status and on the trans-sulphuration pathway in mouse liver. Mice were divided into three groups: control; treated daily with aspartame for 90 days; and treated with aspartame plus N-acetylcysteine (NAC). Chronic administration of aspartame increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase activities and caused liver injury as well as marked decreased hepatic levels of reduced glutathione (GSH), oxidized glutathione (GSSG), γ-glutamylcysteine ​​(γ-GC), and most metabolites of the trans-sulphuration pathway, such as cysteine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine ​​(SAH). Aspartame also triggered a decrease in mRNA and protein levels of the catalytic subunit of glutamate cysteine ligase (GCLc) and cystathionine γ-lyase, and in protein levels of methionine adenosyltransferase 1A and 2A. N-acetylcysteine prevented the aspartame-induced liver injury and the increase in plasma ALT activity as well as the decrease in GSH, γ-GC, cysteine, SAM and SAH levels and GCLc protein levels. In conclusion, chronic administration of aspartame caused marked hepatic GSH depletion, which should be ascribed to GCLc down-regulation and decreased cysteine levels. Aspartame triggered blockade of the trans-sulphuration pathway at two steps, cystathionine γ-lyase and methionine adenosyltransferases. NAC restored glutathione levels as well as the impairment of the trans-sulphuration pathway.
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
authors.forename: Isabela
authors.initials: I
authors.lastname: Finamor
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Pérez
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Santa Maria, Av. Roraima, 1000, 97105900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Bressan
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Santa Maria, Av. Roraima, 1000, 97105900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Brenner
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Rius-Pérez
authors.affiliation: University Hospital of Santa Maria, Federal University of Santa Maria,, Av. Roraima, 1000, 97105900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brittes
authors.affiliation: Department of Morphology, Federal University of Santa Maria, Av. Roraima, 1000, 97105900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Cheiran
authors.affiliation: Department of Morphology, Federal University of Santa Maria, Av. Roraima, 1000, 97105900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Rocha
authors.affiliation: Department of Morphology, Federal University of Santa Maria, Av. Roraima, 1000, 97105900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: da Veiga
authors.affiliation: Department of Physiology, Faculty of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Sastre
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Santa Maria, Av. Roraima, 1000, 97105900 Santa Maria, Rio Grande do Sul, Brazil.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pavanato
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D001218:Aspartame / Q000008:administration & dosage / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D003542:Cystathionine gamma-Lyase / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008716:Methionine Adenosyltransferase / Q000235:genetics; D051379:Mice; D013549:Sweetening Agents / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D013549:Sweetening Agents; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase; D003542:Cystathionine gamma-Lyase; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D000111:Acetylcysteine; D001218:Aspartame
keywords: Aspartame; Cysteine; N-acetylcysteine; S-adenosylmethionine