title: Mitochondrial respiratory dysfunction due to the conversion of substituted cathinones to methylbenzamides in SH-SY5Y cells.
abstract: The increased use of cathinone-type designer drugs, known as legal highs, has led to concerns about their potential neurotoxicity due to their similarity to methamphetamine (METH). Therefore, closer investigations of their toxic effects are needed. We investigated the effects of the cathinones 4-methylmethcathinone (4-MMC) and 3,4-methylenedioxymethcathinone (MDMC) and the amphetamine METH on cytotoxicity and mitochondrial respiration in SH-SY5Y neuroblastoma cells. We also investigated the contribution of reactive species, dopamine, Bcl-2 and tumor necrosis factor α (TNFα) on toxicity. Finally, we investigated the effect of cathinone breakdown products using ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry and studied their involvement in toxicity. We observed dose-dependent increases in cytotoxicity and decreases in mitochondrial respiration following treatment with all cathinones and amphetamines. Glutathione depletion increases amphetamine, but not cathinone toxicity. Bcl-2 and TNFα pathways are involved in toxicity but dopamine levels are not. We also show that cathinones, but not amphetamines, spontaneously produce reactive species and cytotoxic methylbenzamide breakdown products when in aqueous solution. These results provide an important first insight into the mechanisms of cathinone cytotoxicity and pave the way for further studies on cathinone toxicity in vivo.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Biomedicum Helsinki, Haartmaninkatu 8, FI-00014 University of Helsinki, Finland.
authors.forename: Bjørnar
authors.initials: B
authors.lastname: den Hollander
authors.affiliation: Department of Forensic Medicine, Kytösuontie 11, FI-00014 University of Helsinki, Finland.
authors.forename: Mira
authors.initials: M
authors.lastname: Sundström
authors.affiliation: Department of Forensic Medicine, Kytösuontie 11, FI-00014 University of Helsinki, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Pelander
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Biomedicum Helsinki, Haartmaninkatu 8, FI-00014 University of Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Siltanen
authors.affiliation: Department of Forensic Medicine, Kytösuontie 11, FI-00014 University of Helsinki, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Ojanperä
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Biomedicum Helsinki, Haartmaninkatu 8, FI-00014 University of Helsinki, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Mervaala
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Biomedicum Helsinki, Haartmaninkatu 8, FI-00014 University of Helsinki, Finland.
authors.forename: Esa R
authors.initials: ER
authors.lastname: Korpi
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Biomedicum Helsinki, Haartmaninkatu 8, FI-00014 University of Helsinki, Finland.
authors.forename: Esko
authors.initials: E
authors.lastname: Kankuri
mesh_terms: D000470:Alkaloids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008745:Methylation; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D000470:Alkaloids; D001549:Benzamides; C023665:cathinone