Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines)
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10284/10023 |
Resumo: | The use of cathinone designer drugs in recreational settings has been associated with severe toxic effects, including liver damage. The precise mechanisms by which cathinones induce hepatotoxicity and whether they act by common pathways remain to be elucidated. Herein, we assessed the toxicity of the cathinones methylone, pentedrone, 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylethcathinone (4-MEC) in primary rat hepatocytes (PRH) and HepaRG cells, and compared with that of 3,4-methylenedioxymethamphetamine (MDMA). MDPV and pentedrone were significantly more toxic than MDMA, while methylone was the least cytotoxic compound. Importantly, PRH revealed to be the most sensitive experimental model and was thus used to explore the mechanisms underlying the observed toxicity. All drugs elicited the formation of reactive oxygen and nitrogen species (ROS and RNS), but more markedly for methylone, pentedrone and 4-MEC. GSH depletion was also a common effect at the highest concentration tested, whereas only MDPV and pentedrone caused a significant decrease in ATP levels. The antioxidants ascorbic acid or N-acetyl-L-cysteine partially attenuated the observed cell death. All cathinones triggered significant caspase activation and apoptosis, which was partially reversed by the caspase inhibitor Ac-LETD-CHO. In conclusion, the present data shows that (1) cathinones induce in vitro hepatotoxic effects that vary in magnitude among the different analogues, (2) oxidative stress and mitochondrial dysfunction play a role in cathinones-induced hepatic injury, and (3) apoptosis appears to be an important pathway of cell death elicited by these novel drugs. |
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Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines)Synthetic cathinonesβ-keto amphetaminesHepatotoxicityOxidative stressApoptosisThe use of cathinone designer drugs in recreational settings has been associated with severe toxic effects, including liver damage. The precise mechanisms by which cathinones induce hepatotoxicity and whether they act by common pathways remain to be elucidated. Herein, we assessed the toxicity of the cathinones methylone, pentedrone, 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylethcathinone (4-MEC) in primary rat hepatocytes (PRH) and HepaRG cells, and compared with that of 3,4-methylenedioxymethamphetamine (MDMA). MDPV and pentedrone were significantly more toxic than MDMA, while methylone was the least cytotoxic compound. Importantly, PRH revealed to be the most sensitive experimental model and was thus used to explore the mechanisms underlying the observed toxicity. All drugs elicited the formation of reactive oxygen and nitrogen species (ROS and RNS), but more markedly for methylone, pentedrone and 4-MEC. GSH depletion was also a common effect at the highest concentration tested, whereas only MDPV and pentedrone caused a significant decrease in ATP levels. The antioxidants ascorbic acid or N-acetyl-L-cysteine partially attenuated the observed cell death. All cathinones triggered significant caspase activation and apoptosis, which was partially reversed by the caspase inhibitor Ac-LETD-CHO. In conclusion, the present data shows that (1) cathinones induce in vitro hepatotoxic effects that vary in magnitude among the different analogues, (2) oxidative stress and mitochondrial dysfunction play a role in cathinones-induced hepatic injury, and (3) apoptosis appears to be an important pathway of cell death elicited by these novel drugs.Oxford University PressRepositório Institucional da Universidade Fernando PessoaValente, Maria JoãoAraújo, Ana MargaridaBastos, Maria de LourdesFernandes, EduardaCarvalho, FélixGuedes de Pinho, PaulaCarvalho, Márcia2021-07-02T11:54:49Z2016-01-01T00:00:00Z2016-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10284/10023eng1096-608010.1093/toxsci/kfw1051096-0929metadata 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:RCAAP2022-09-06T02:09:19Zoai:bdigital.ufp.pt:10284/10023Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T15:46:47.905236Repositório 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 |
Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines) |
title |
Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines) |
spellingShingle |
Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines) Valente, Maria João Synthetic cathinones β-keto amphetamines Hepatotoxicity Oxidative stress Apoptosis |
title_short |
Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines) |
title_full |
Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines) |
title_fullStr |
Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines) |
title_full_unstemmed |
Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines) |
title_sort |
Editor’s highlight: characterization of hepatotoxicity mechanisms triggered by designer cathinone drugs (β-Keto amphetamines) |
author |
Valente, Maria João |
author_facet |
Valente, Maria João Araújo, Ana Margarida Bastos, Maria de Lourdes Fernandes, Eduarda Carvalho, Félix Guedes de Pinho, Paula Carvalho, Márcia |
author_role |
author |
author2 |
Araújo, Ana Margarida Bastos, Maria de Lourdes Fernandes, Eduarda Carvalho, Félix Guedes de Pinho, Paula Carvalho, Márcia |
author2_role |
author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Institucional da Universidade Fernando Pessoa |
dc.contributor.author.fl_str_mv |
Valente, Maria João Araújo, Ana Margarida Bastos, Maria de Lourdes Fernandes, Eduarda Carvalho, Félix Guedes de Pinho, Paula Carvalho, Márcia |
dc.subject.por.fl_str_mv |
Synthetic cathinones β-keto amphetamines Hepatotoxicity Oxidative stress Apoptosis |
topic |
Synthetic cathinones β-keto amphetamines Hepatotoxicity Oxidative stress Apoptosis |
description |
The use of cathinone designer drugs in recreational settings has been associated with severe toxic effects, including liver damage. The precise mechanisms by which cathinones induce hepatotoxicity and whether they act by common pathways remain to be elucidated. Herein, we assessed the toxicity of the cathinones methylone, pentedrone, 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylethcathinone (4-MEC) in primary rat hepatocytes (PRH) and HepaRG cells, and compared with that of 3,4-methylenedioxymethamphetamine (MDMA). MDPV and pentedrone were significantly more toxic than MDMA, while methylone was the least cytotoxic compound. Importantly, PRH revealed to be the most sensitive experimental model and was thus used to explore the mechanisms underlying the observed toxicity. All drugs elicited the formation of reactive oxygen and nitrogen species (ROS and RNS), but more markedly for methylone, pentedrone and 4-MEC. GSH depletion was also a common effect at the highest concentration tested, whereas only MDPV and pentedrone caused a significant decrease in ATP levels. The antioxidants ascorbic acid or N-acetyl-L-cysteine partially attenuated the observed cell death. All cathinones triggered significant caspase activation and apoptosis, which was partially reversed by the caspase inhibitor Ac-LETD-CHO. In conclusion, the present data shows that (1) cathinones induce in vitro hepatotoxic effects that vary in magnitude among the different analogues, (2) oxidative stress and mitochondrial dysfunction play a role in cathinones-induced hepatic injury, and (3) apoptosis appears to be an important pathway of cell death elicited by these novel drugs. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-01-01T00:00:00Z 2016-01-01T00:00:00Z 2021-07-02T11:54:49Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10284/10023 |
url |
http://hdl.handle.net/10284/10023 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1096-6080 10.1093/toxsci/kfw105 1096-0929 |
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metadata only access info:eu-repo/semantics/openAccess |
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metadata only access |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Oxford University Press |
publisher.none.fl_str_mv |
Oxford University Press |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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