From street to lab: in vitro hepatotoxicity of buphedrone, butylone and 3,4-DMMC

Abstract

Synthetic cathinones are among the most popular new psychoactive substances, being abused for their stimulant properties, which are similar to those of amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). Considering that the liver is a likely target for cathinones-induced toxicity, and for their metabolic activation/detoxification, we aimed to determine the hepatotoxicity of three commonly abused synthetic cathinones: butylone, α-methylamino-butyrophenone (buphedrone) and 3,4-dimethylmethcathinone (3,4-DMMC). We characterized their cytotoxic profile in primary rat hepatocytes (PRH) and in the HepaRG and HepG2 cell lines. PRH was the most sensitive cell model, showing the lowest EC50 values for all three substances (0.158 mM for 3,4-DMMC; 1.21 mM for butylone; 1.57 mM for buphedrone). Co-exposure of PRH to the synthetic cathinones and CYP450 inhibitors (selective and non-selective) proved that hepatic metabolism reduced the toxicity of buphedrone but increased that of butylone and 3,4-DMMC. All compounds were able to increase oxidative stress, disrupting mitochondrial homeostasis and inducing apoptotic and necrotic features, while also increasing the occurrence of acidic vesicular organelles in PRH, compatible with autophagic activation. In conclusion, butylone, buphedrone and 3,4-DMMC have hepatotoxic potential, and their toxicity lies in the interference with a number of homeostatic processes, while being influenced by their metabolic fate.

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Funding

This work was financed by FEDER funds through the COMPETE 2020—Operational Programme for Competitiveness and Internationalisation (POCI), and by Portuguese funds through FCT (Fundação para a Ciência e a Tecnologia) in the framework of the project POCI-01-0145-FEDER-029584. This work was also supported by the Applied Molecular Biosciences Unit—UCIBIO which is financed by national funds from FCT (UIDP/04378/2020 and UIDB/04378/2020).

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Correspondence to Rita Roque Bravo or Diana Dias da Silva.

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All procedures involving animals were executed considering the highest standards of ethics, taking into consideration international, national and/or institutional guidelines. Procedures were performed after approval by the local Ethical Committee for the Welfare of Experimental Animals (University of Porto-ORBEA; project 158/2014) and by the national authority Direção Geral de Alimentação e Veterinária (DGAV).

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Roque Bravo, R., Carmo, H., Valente, M.J. et al. From street to lab: in vitro hepatotoxicity of buphedrone, butylone and 3,4-DMMC. Arch Toxicol (2021). https://doi.org/10.1007/s00204-021-02990-9

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Keywords

  • New psychoactive substances (NPS)
  • Liver toxicity
  • CYP2D6
  • CYP3A4
  • CYP2E1
  • Apoptosis
  • Necrosis
  • Autophagy