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Open AccessArticle

Para-Halogenation of Amphetamine and Methcathinone Increases the Mitochondrial Toxicity in Undifferentiated and Differentiated SH-SY5Y Cells

1
Division of Clinical Pharmacology & Toxicology, University Hospital Basel, 4031 Basel, Switzerland
2
Department of Biomedicine, University of Basel, 4031 Basel, Switzerland
3
Swiss Centre for Applied Human Toxicology, 4031 Basel, Switzerland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(8), 2841; https://doi.org/10.3390/ijms21082841
Received: 14 March 2020 / Revised: 14 April 2020 / Accepted: 15 April 2020 / Published: 18 April 2020
(This article belongs to the Section Molecular Toxicology)
Halogenation of amphetamines and methcathinones has become a common method to obtain novel psychoactive substances (NPS) also called “legal highs”. The para-halogenated derivatives of amphetamine and methcathinone are available over the internet and have entered the illicit drug market but studies on their potential neurotoxic effects are rare. The primary aim of this study was to explore the neurotoxicity of amphetamine, methcathinone and their para-halogenated derivatives 4-fluoroamphetamine (4-FA), 4-chloroamphetamine (PCA), 4-fluoromethcathinone (4-FMC), and 4-chloromethcathinone (4-CMC) in undifferentiated and differentiated SH-SY5Y cells. We found that 4-FA, PCA, and 4-CMC were cytotoxic (decrease in cellular ATP and plasma membrane damage) for both cell types, whereby differentiated cells were less sensitive. IC50 values for cellular ATP depletion were in the range of 1.4 mM for 4-FA, 0.4 mM for PCA and 1.4 mM for 4-CMC. The rank of cytotoxicity observed for the para-substituents was chloride > fluoride > hydrogen for both amphetamines and cathinones. Each of 4-FA, PCA and 4-CMC decreased the mitochondrial membrane potential in both cell types, and PCA and 4-CMC impaired the function of the electron transport chain of mitochondria in SH-SY5Y cells. 4-FA, PCA, and 4-CMC increased the ROS level and PCA and 4-CMC induced apoptosis by the endogenous pathway. In conclusion, para-halogenation of amphetamine and methcathinone increases their neurotoxic properties due to the impairment of mitochondrial function and induction of apoptosis. Although the cytotoxic concentrations were higher than those needed for pharmacological activity, the current findings may be important regarding the uncontrolled recreational use of these compounds. View Full-Text
Keywords: amphetamine; methcathinone; mitochondria; neurotoxicity; para-halogenation amphetamine; methcathinone; mitochondria; neurotoxicity; para-halogenation
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MDPI and ACS Style

Zhou, X.; Bouitbir, J.; Liechti, M.E.; Krähenbühl, S.; Mancuso, R.V. Para-Halogenation of Amphetamine and Methcathinone Increases the Mitochondrial Toxicity in Undifferentiated and Differentiated SH-SY5Y Cells. Int. J. Mol. Sci. 2020, 21, 2841. https://doi.org/10.3390/ijms21082841

AMA Style

Zhou X, Bouitbir J, Liechti ME, Krähenbühl S, Mancuso RV. Para-Halogenation of Amphetamine and Methcathinone Increases the Mitochondrial Toxicity in Undifferentiated and Differentiated SH-SY5Y Cells. International Journal of Molecular Sciences. 2020; 21(8):2841. https://doi.org/10.3390/ijms21082841

Chicago/Turabian Style

Zhou, Xun; Bouitbir, Jamal; Liechti, Matthias E.; Krähenbühl, Stephan; Mancuso, Riccardo V. 2020. "Para-Halogenation of Amphetamine and Methcathinone Increases the Mitochondrial Toxicity in Undifferentiated and Differentiated SH-SY5Y Cells" Int. J. Mol. Sci. 21, no. 8: 2841. https://doi.org/10.3390/ijms21082841

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