Effects of 7-hydroxymitragynine on serotonin, amino acid profiles, and ion homeostasis in SH-SY5Y cells.

7-Hydroxymitragynine (7-HMG), an indole-based alkaloid obtained from Mitragyna speciosa Korth, is also formed through hepatic cytochrome P450 (CYP450)-mediated metabolism of mitragynine in humans and exhibits strong neuromodulatory activity, but its cellular biological effects on neuronal systems remain insufficiently defined. In this study, we investigated the biochemical and ion-omic responses of SH-SY5Y neuroblastoma cells following 7-HMG exposure. Metabolite profiling revealed significant elevations in multiple intracellular amino acids, including Asp, Gly, Gln, Ser, Met, Leu, Lys, Thr, Val, and Tyr, suggesting alterations in amino acid metabolism associated with cellular stress responses. Notably, intracellular serotonin (5-HT) levels decreased while extracellular 5-HT concentrations increased, suggesting dysregulation of serotonin storage and release mechanisms. ICP-MS analysis demonstrated substantial alterations in Ca²⁺ and Mg²⁺ homeostasis, with increases in intracellular Ca²⁺ and Mg²⁺, along with elevated extracellular Mg²⁺. These changes indicate perturbation of ion-transport systems and intracellular signaling processes relevant to neuronal function. Together, these findings show that 7-HMG induced significant metabolic and ionic disturbances in neuronal cells, providing new mechanistic insight into its neurobiological activity and potential neurotoxicity.