Differentially altered phytochemical composition contributes to the pharmaco-toxicological conundrum of oleander.

Nerium oleander L. is utilized in Ayurveda and Chinese traditional medicine to address diabetes and metabolic liver disease. However, oleander represents a bizarre paradox in evidence-based medicine since, despite several pre-clinical and clinical toxicological reports, oleander is extensively utilized in traditional medicine. We hypothesized that the dual pharmaco-toxicological activity of oleander is due to the variations in the phytochemical profile. This variance is likely due to the oleander variety (white or red) or the solvent extraction process. To test this hypothesis, leaves of both varieties of oleander were collected from multiple geographical locations to eliminate chances of phytochemical variation due to environmental and abiotic factors. Phytochemical profiling of polar and non-polar extracts of oleander was performed using GC-MS and LC-MS. Oleandrin content was measured using HPLC. Untargeted metabolomics data were subjected to metabolite class and metabolic pathway enrichment analysis. Comparative cytotoxicity was evaluated using Caco-2 and PBMC cells. Results showed that the phytochemical compositions are strongly influenced by the plant variety and solvent extraction technique. Red oleander and methanolic extracts demonstrated an elevated concentration of toxic oleandrin and cerebrin. While white oleander exhibited low levels of oleandrin, it contained higher levels of tocopherol and phytol. Methanol extracts exhibited enhanced cytotoxicity on Caco-2 cells and PBMCs, which correlated with oleandrin concentrations. Diverse metabolic pathways, such as phenylpropanoid production, differed among extracts. In conclusion, the polar extracts of red oleander present a significant risk of toxicity due to high oleandrin levels, and safer alternatives include non-polar extracts from white oleander.