title: Modulation of methylmercury uptake by methionine: prevention of mitochondrial dysfunction in rat liver slices by a mimicry mechanism.
abstract: Methylmercury (MeHg) is an ubiquitous environmental pollutant which is transported into the mammalian cells when present as the methylmercury-cysteine conjugate (MeHg-Cys). With special emphasis on hepatic cells, due to their particular propensity to accumulate an appreciable amount of Hg after exposure to MeHg, this study was performed to evaluate the effects of methionine (Met) on Hg uptake, reactive species (RS) formation, oxygen consumption and mitochondrial function/cellular viability in both liver slices and mitochondria isolated from these slices, after exposure to MeHg or the MeHg-Cys complex. The liver slices were pre-treated with Met (250 μM) 15 min before being exposed to MeHg (25 μM) or MeHg-Cys (25 μM each) for 30 min at 37 °C. The treatment with MeHg caused a significant increase in the Hg concentration in both liver slices and mitochondria isolated from liver slices. Moreover, the Hg uptake was higher in the group exposed to the MeHg-Cys complex. In the DCF (dichlorofluorescein) assay, the exposure to MeHg and MeHg-Cys produced a significant increase in DFC reactive species (DFC-RS) formation only in the mitochondria isolated from liver slices. As observed with Hg uptake, DFC-RS levels were significantly higher in the mitochondria treated with the MeHg-Cys complex compared to MeHg alone. MeHg exposure also caused a marked decrease in the oxygen consumption of liver slices when compared to the control group, and this effect was more pronounced in the liver slices treated with the MeHg-Cys complex. Similarly, the loss of mitochondrial activity/cell viability was greater in liver slices exposed to the MeHg-Cys complex when compared to slices treated only with MeHg. In all studied parameters, Met pre-treatment was effective in preventing the MeHg- and/or MeHg-Cys-induced toxicity in both liver slices and mitochondria. Part of the protection afforded by Met against MeHg may be related to a direct interaction with MeHg or to the competition of Met with the complex formed between MeHg and endogenous cysteine. In summary, our results show that Met pre-treatment produces pronounced protection against the toxic effects induced by MeHg and/or the MeHg-Cys complex on mitochondrial function and cell viability. Consequently, this amino acid offers considerable promise as a potential agent for treating acute MeHg exposure.
authors.affiliation: Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, CEP 97105-900, Brazil.
authors.forename: Daniel Henrique
authors.initials: DH
authors.lastname: Roos
authors.forename: Robson Luiz
authors.initials: RL
authors.lastname: Puntel
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
authors.forename: Denise
authors.initials: D
authors.lastname: Bohrer
authors.forename: João Batista T
authors.initials: JB
authors.lastname: Rocha
authors.forename: Nilda B
authors.initials: NB
authors.lastname: de Vargas Barbosa
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002274:Carcinogens, Environmental / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000737:chemistry / Q000502:physiology*; D008767:Methylmercury Compounds / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology*; D018716:Molecular Mimicry / Q000502:physiology*; D009924:Organ Culture Techniques; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002274:Carcinogens, Environmental; D008767:Methylmercury Compounds; D008715:Methionine