Toxicity and Its Mechanism Study of Arecae semen Aqueous Extract in Wistar Rats by UPLC-HDMS-Based Serum Metabolomics

Background. Arecae semen (AS) is officially recorded in Chinese Pharmacopoeia and it is known for its multiple functions, including antidepressive, antioxidant, anti-inflammatory, and cholesterol-lowering effects, which have been confirmed by modern pharmacological study. Previous study in our laboratory showed that long-term oral administration of Arecae semen aqueous extract (ASAE) at high dosage was toxic. However, the underlying toxicological mechanism of AS is not yet clear at the biochemistry level. Hypothesis. The aim of this work was to characterize the metabolome, evaluate the metabolic changes, and study the mechanisms of the toxicity induced by different treatment doses of ASAE via metabolomics. Methods. Wistar rats were administered orally two different doses of ASAE (1500 and 4500 mg/kg/d) for 30 days. The investigation was carried out to evaluate the safety of ASAE. And, the UPLC-HDMS-based serum metabolomics in conjunction with multivariate statistical techniques was applied to investigate the serum metabolite profile and potential markers of toxicity induced by different doses of ASAE. Results. Coupled with blood biochemistry and histopathology results, the significant difference in metabolic profiling was observed between 1500 and 4500 mg/kg/d dosages of ASAE-treated rats and normal rats by using pattern recognition analysis, indicating that changes in serum metabolites must have occurred. Some significant changed metabolites such as arachidonic acid, linoleic acid, stearic acid, and LPC (18 : 1) have been found and identified. These biochemical changes in serum metabolites are related to the perturbation of linoleic acid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, and purine metabolism, which may be helpful to further understand the cardiotoxicity and neurotoxicity of ASAE. Conclusion. The study shows that the metabolomic method may be a valuable tool for studying the essence of toxicity induced by traditional Chinese medicine.