Den Hollander 2014 Toxicol Sci
| den Hollander B, SundstrΓΆm M, Pelander A, OjanperΓ€ I, Mervaala E, Korpi ER, Kankuri E (2014) Keto amphetamine toxicity - focus on the redox reactivity of the cathinone designer drug mephedrone. Toxicol Sci 141:120-31. |
den Hollander B, Sundstrom M, Pelander A, Ojanpera I, Mervaala E, Korpi ER, Kankuri E (2014) Toxicol Sci
Abstract: The Ξ²-keto amphetamine (cathinone, Ξ²-KA) designer drugs such as mephedrone (4-methylmethcathinone, 4-MMC) show a large degree of structural similarity to amphetamines like methamphetamine (METH). However, little is currently known about whether these substances also share the potential neurotoxic properties of their non-keto amphetamine counterparts, or what mechanisms could be involved. Here, we evaluate the cytotoxicity of Ξ²-KAs in SH-SY5Y cells using lactate dehydrogenase (LDH) assays, assess the redox potential of a range of Ξ²-KAs and non-keto amphetamines using the sensitive redox indicator 2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) and explore the effect of 4-MMC on the formation of protein adducts using ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) and on the mitochondrial respiratory chain using high resolution respirometry. We show that treatment with Ξ²-KAs increases LDH release. Further, we demonstrate that even under physiological pH, Ξ²-KAs are effective and selective-as compared to their non-keto analogues-reductants in the presence of electron acceptors. Increased pH (range 7.6-8.0) greatly enhanced the reactivity up to six-fold. We found no evidence of protein adduct formation, suggesting the reactivity is due to direct electron transfer by the Ξ²-KAs. Finally, we show that 4-MMC and METH produce dissimilar effects on the respiratory chain. Our results indicate that Ξ²-KAs such as 4-MMC possess cytotoxic properties in vitro. Furthermore, in the presence of an electron-accepting redox partner, the ketone moiety of Ξ²-KAs is vital for pH-dependent redox reactivity. Further work is needed to establish the importance of Ξ²-KA redox properties and its potential toxicological importance in vivo. β’ Keywords: Cathinones, Mephedrone, Methamphetamine, Neurotoxicity, Protein adducts, Reducing agent, Respiratory chain, Ξ²-keto amphetamine
β’ O2k-Network Lab: FI Helsinki Mervaala E
Labels: MiParea: Respiration
Organism: Mouse
Tissue;cell: Nervous system
Preparation: Homogenate
Coupling state: LEAK, OXPHOS, ET
Pathway: N, S, NS, ROX
HRR: Oxygraph-2k
