The cytotoxicity of synthetic cathinones on dopaminergic-differentiated SH-SY5Y neuroblastoma cell line: Exploring the role of β-keto metabolic reduction.

Synthetic cathinones, a major class of new psychoactive substances (NPS), pose a growing public health threat due to their widespread recreational use, particularly among young people. While metabolism significantly influences xenobiotic toxicity, its role in synthetic cathinone neurotoxicity remains underexplored. Similarly to the other cathinones included in this study, 4-CBC and 3-CBC were rapidly metabolized in vitro (t1/2 < 20 min), producing dihydro-metabolites as major products. To evaluate the toxicological relevance of this transformation, we synthesized ten dihydro-metabolites and assessed their cytotoxicity in differentiated SH-SY5Y cells. Most dihydro-derivatives were more neurotoxic than their parent cathinones, with dihydro-3-CBC, dihydro-3-CIC, dihydro-4-CIC, and dihydro-4-CBC displaying the lowest LC50 values (0.24-0.28 mM). All dihydro-metabolites exhibited higher Hill slopes, indicating that small increases in their formation might result in significant toxicological consequences. Dihydro-α-PHP showed the steepest slope, raising concern given the high use and seizure rates of α-PHP in the Portuguese Azores and Madeira islands. These findings highlight the importance of β-ketone reduction in synthetic cathinone toxicity and suggest that similar metabolic transformations may contribute to the toxicity of other chemical agents.