Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations

Detalhes bibliográficos
Autor(a) principal: Araújo, Ana Margarida
Data de Publicação: 2019
Outros Autores: Carvalho, Márcia, Bastos, Maria de Lourdes, Carvalho, Félix, Guedes de Pinho, Paula
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10284/9978
Resumo: Methylone (3,4-methylenedioxymethcathinone) is one of the most popular new psychoactive drugs worldwide. Although advertised as a safe drug, its use has been associated to several cases of liver damage. In this work, a metabolomics approach based on gas chromatography-mass spectrometry (GC-MS) combined with chemometric analyses was used to characterize the disturbances occurring in the intra- and extracellular metabolome of primary mouse hepatocytes exposed to two subtoxic concentrations (LC01 and LC10) of methylone to better understand the early hepatotoxic events. Results showed a characteristic metabolic fingerprint for methylone, where aspartate, cysteine, 2-methyl-1-pentanol, 4-methylheptane, dodecane, 2,4-dimethyl-1-heptene, 1,3-di-tert-butylbenzene, acetophenone, formaldehyde and glyoxal levels were significantly changed at both concentrations tested. Furthermore, subtoxic concentrations of methylone caused profound changes in several biochemical pathways, suggesting adaptations in energy production processes (TCA cycle, amino acids metabolism and pyruvate metabolism), cellular antioxidant defenses (glutamate, cysteine and glutathione metabolism) and hepatic enzymes (associated to hydrocarbons, alcohols, aldehydes and ketones metabolism). This metabolic response to the initial methylone challenge most probably reflects the activation of protective mechanisms to restore cellular homeostasis. Overall, this study highlights the potential of untargeted metabolomic analysis to reveal the hepatic metabolic signature of methylone at subtoxic concentrations, and also provides clues to clarify the early mechanisms underlying the toxicity triggered by this new psychoactive substance, opening a new perspective for the study of toxicity mechanisms of new xenobiotics.
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spelling Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrationsPrimary mouse hepatocytesMethyloneMetabolomicsGC–MSHepatotoxicityIntracellular and extracellular metabolite profilingMethylone (3,4-methylenedioxymethcathinone) is one of the most popular new psychoactive drugs worldwide. Although advertised as a safe drug, its use has been associated to several cases of liver damage. In this work, a metabolomics approach based on gas chromatography-mass spectrometry (GC-MS) combined with chemometric analyses was used to characterize the disturbances occurring in the intra- and extracellular metabolome of primary mouse hepatocytes exposed to two subtoxic concentrations (LC01 and LC10) of methylone to better understand the early hepatotoxic events. Results showed a characteristic metabolic fingerprint for methylone, where aspartate, cysteine, 2-methyl-1-pentanol, 4-methylheptane, dodecane, 2,4-dimethyl-1-heptene, 1,3-di-tert-butylbenzene, acetophenone, formaldehyde and glyoxal levels were significantly changed at both concentrations tested. Furthermore, subtoxic concentrations of methylone caused profound changes in several biochemical pathways, suggesting adaptations in energy production processes (TCA cycle, amino acids metabolism and pyruvate metabolism), cellular antioxidant defenses (glutamate, cysteine and glutathione metabolism) and hepatic enzymes (associated to hydrocarbons, alcohols, aldehydes and ketones metabolism). This metabolic response to the initial methylone challenge most probably reflects the activation of protective mechanisms to restore cellular homeostasis. Overall, this study highlights the potential of untargeted metabolomic analysis to reveal the hepatic metabolic signature of methylone at subtoxic concentrations, and also provides clues to clarify the early mechanisms underlying the toxicity triggered by this new psychoactive substance, opening a new perspective for the study of toxicity mechanisms of new xenobiotics.SpringerRepositório Institucional da Universidade Fernando PessoaAraújo, Ana MargaridaCarvalho, MárciaBastos, Maria de LourdesCarvalho, FélixGuedes de Pinho, Paula2021-06-30T10:54:22Z2019-01-01T00:00:00Z2019-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10284/9978eng0340-576110.1007/s00204-019-02566-81432-0738metadata only accessinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-09-06T02:09:16Zoai:bdigital.ufp.pt:10284/9978Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T15:46:45.502815Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations
title Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations
spellingShingle Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations
Araújo, Ana Margarida
Primary mouse hepatocytes
Methylone
Metabolomics
GC–MS
Hepatotoxicity
Intracellular and extracellular metabolite profiling
title_short Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations
title_full Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations
title_fullStr Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations
title_full_unstemmed Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations
title_sort Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations
author Araújo, Ana Margarida
author_facet Araújo, Ana Margarida
Carvalho, Márcia
Bastos, Maria de Lourdes
Carvalho, Félix
Guedes de Pinho, Paula
author_role author
author2 Carvalho, Márcia
Bastos, Maria de Lourdes
Carvalho, Félix
Guedes de Pinho, Paula
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Repositório Institucional da Universidade Fernando Pessoa
dc.contributor.author.fl_str_mv Araújo, Ana Margarida
Carvalho, Márcia
Bastos, Maria de Lourdes
Carvalho, Félix
Guedes de Pinho, Paula
dc.subject.por.fl_str_mv Primary mouse hepatocytes
Methylone
Metabolomics
GC–MS
Hepatotoxicity
Intracellular and extracellular metabolite profiling
topic Primary mouse hepatocytes
Methylone
Metabolomics
GC–MS
Hepatotoxicity
Intracellular and extracellular metabolite profiling
description Methylone (3,4-methylenedioxymethcathinone) is one of the most popular new psychoactive drugs worldwide. Although advertised as a safe drug, its use has been associated to several cases of liver damage. In this work, a metabolomics approach based on gas chromatography-mass spectrometry (GC-MS) combined with chemometric analyses was used to characterize the disturbances occurring in the intra- and extracellular metabolome of primary mouse hepatocytes exposed to two subtoxic concentrations (LC01 and LC10) of methylone to better understand the early hepatotoxic events. Results showed a characteristic metabolic fingerprint for methylone, where aspartate, cysteine, 2-methyl-1-pentanol, 4-methylheptane, dodecane, 2,4-dimethyl-1-heptene, 1,3-di-tert-butylbenzene, acetophenone, formaldehyde and glyoxal levels were significantly changed at both concentrations tested. Furthermore, subtoxic concentrations of methylone caused profound changes in several biochemical pathways, suggesting adaptations in energy production processes (TCA cycle, amino acids metabolism and pyruvate metabolism), cellular antioxidant defenses (glutamate, cysteine and glutathione metabolism) and hepatic enzymes (associated to hydrocarbons, alcohols, aldehydes and ketones metabolism). This metabolic response to the initial methylone challenge most probably reflects the activation of protective mechanisms to restore cellular homeostasis. Overall, this study highlights the potential of untargeted metabolomic analysis to reveal the hepatic metabolic signature of methylone at subtoxic concentrations, and also provides clues to clarify the early mechanisms underlying the toxicity triggered by this new psychoactive substance, opening a new perspective for the study of toxicity mechanisms of new xenobiotics.
publishDate 2019
dc.date.none.fl_str_mv 2019-01-01T00:00:00Z
2019-01-01T00:00:00Z
2021-06-30T10:54:22Z
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10.1007/s00204-019-02566-8
1432-0738
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