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Publicação
Efeitos biológicos de novas substâncias psicoativas
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Resumo(s)
O consumo de Novas Substâncias Psicoativas (NSP) tem aumentado globalmente,
representando um desafio significativo à saúde pública. Até dezembro de 2023, a Agência da União
Europeia sobre Drogas (EUDA) identificou 950 NSP, incluindo catinonas sintéticas. Estas drogas estão
associadas a efeitos tóxicos graves e mortes, sublinhando a necessidade urgente de estudos aprofundados
sobre o seu perfil toxicológico e mecanismos de ação de modo a clarificar o seu impacto no organismo.
Este trabalho centrou-se no estudo de quatro catinonas sintéticas, 3-CIC, 4-CIC, 3-Cl-TBC
(bupropiona) e 4-Cl-TBC, quanto à sua biodisponibilidade gastrointestinal num modelo celular
intestinal, Caco-2, e mecanismos de citotoxicidade num modelo celular hepático, HepG2. Foram
analisados, em particular, a produção de espécies reativas ao oxigénio (ROS) e os efeitos na membrana
celular sobre a libertação da lactato desidrogenase (LDH), bem como as alterações no perfil proteico
induzidas pela exposição ao stress oxidativo.
Os ensaios de citotoxicidade demonstraram valores de IC50 entre 2,5 e 6,2 mM para Caco-2,
sendo a 4-Cl-TBC a catinona que mostrou maior toxicidade. Para 3-CIC e 4-CIC, os mecanismos de
toxicidade foram associados a danos na membrana celular e aumento de ROS, enquanto que 3-Cl-TBC
e 4-Cl-TBC apresentaram efeitos mais moderados. Quanto à permeabilidade gastrointestinal, os
coeficientes de permeabilidade aparente (Papp) variaram entre 0,19x10⁻⁶ cm/s e 3,84x10⁻⁶ cm/s, com 3-
CIC mostrando maior permeabilidade e 4-Cl-TBC a menor. Em HepG2, alterações na análise preliminar
de expressão proteica, sugeriram respostas adaptativas ao stress oxidativo, especialmente nas células
expostas à 3-CIC.
Este estudo revela os efeitos tóxicos das catinonas sintéticas, destacando diferenças na sua
citotoxicidade e permeabilidade. Enfatiza a importância de investigar alterações proteicas e propõe
direções para pesquisas futuras sobre os mecanismos de toxicidade, visando uma melhor compreensão
dos riscos e o desenvolvimento de estratégias de controlo mais eficazes.
The consumption of New Psychoactive Substances (NPS) has been increasing globally, posing a significant public health challenge. By December 2023, the European Union Drugs Agency (EUDA) identified 950 NPS, including synthetic cathinones. These drugs are associated with severe toxic effects and deaths, highlighting the urgent need for in-depth studies on their toxicological profiles and mechanisms of action to clarify their impact on the body. This study focused on the analysis of four synthetic cathinones – 3-CIC, 4-CIC, 3-Cl-TBC (bupropion), and 4-Cl-TBC – regarding their gastrointestinal bioavailability in a Caco-2 intestinal cell model and cytotoxicity mechanisms in a HepG2 hepatic cell model. Specifically, the production of reactive oxygen species (ROS) and the effects on the cell membrane, such as lactate dehydrogenase (LDH) release, as well as changes in the protein profile induced by oxidative stress exposure, were analyzed. Cytotoxicity assays showed IC50 values between 2,5 and 6,2 mM for Caco-2, with 4-Cl-TBC exhibiting the highest toxicity. For 3-CIC and 4-CIC, toxicity mechanisms were associated with membrane damage and increased ROS levels, while 3-Cl-TBC and 4-Cl-TBC exhibited more moderate effects. Regarding gastrointestinal permeability, apparent permeability coefficients (Papp) ranged from 0,19x10⁻⁶ cm/s to 3,84x10⁻⁶ cm/s, with 3-CIC showing the highest permeability and 4-Cl-TBC the lowest. In HepG2, preliminary analysis of protein expression suggested adaptive responses to oxidative stress, particularly in cells exposed to 3-CIC. This study reveals the toxic effects of synthetic cathinones, highlighting differences in their cytotoxicity and permeability. It emphasizes the importance of investigating protein alterations and proposes future research directions on toxicity mechanisms, aiming for a better understanding of the risks and the development of more effective control strategies.
The consumption of New Psychoactive Substances (NPS) has been increasing globally, posing a significant public health challenge. By December 2023, the European Union Drugs Agency (EUDA) identified 950 NPS, including synthetic cathinones. These drugs are associated with severe toxic effects and deaths, highlighting the urgent need for in-depth studies on their toxicological profiles and mechanisms of action to clarify their impact on the body. This study focused on the analysis of four synthetic cathinones – 3-CIC, 4-CIC, 3-Cl-TBC (bupropion), and 4-Cl-TBC – regarding their gastrointestinal bioavailability in a Caco-2 intestinal cell model and cytotoxicity mechanisms in a HepG2 hepatic cell model. Specifically, the production of reactive oxygen species (ROS) and the effects on the cell membrane, such as lactate dehydrogenase (LDH) release, as well as changes in the protein profile induced by oxidative stress exposure, were analyzed. Cytotoxicity assays showed IC50 values between 2,5 and 6,2 mM for Caco-2, with 4-Cl-TBC exhibiting the highest toxicity. For 3-CIC and 4-CIC, toxicity mechanisms were associated with membrane damage and increased ROS levels, while 3-Cl-TBC and 4-Cl-TBC exhibited more moderate effects. Regarding gastrointestinal permeability, apparent permeability coefficients (Papp) ranged from 0,19x10⁻⁶ cm/s to 3,84x10⁻⁶ cm/s, with 3-CIC showing the highest permeability and 4-Cl-TBC the lowest. In HepG2, preliminary analysis of protein expression suggested adaptive responses to oxidative stress, particularly in cells exposed to 3-CIC. This study reveals the toxic effects of synthetic cathinones, highlighting differences in their cytotoxicity and permeability. It emphasizes the importance of investigating protein alterations and proposes future research directions on toxicity mechanisms, aiming for a better understanding of the risks and the development of more effective control strategies.
Descrição
Tese de Mestrado, Bioquímica e Biomedicina, 2025, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Catinonas Citotoxicidade Biodisponibilidade Caco-2 HepG2 Teses de mestrado - 2025