Arecoline-Induced Hepatotoxicity in Rats: Screening of Abnormal Metabolic Markers and Potential Mechanisms

Abstract

Arecoline is a pyridine alkaloid derived from areca nut in the Arecaceae family. It has extensive medicinal activity, such as analgesic, anti-inflammatory, and anti-allergic. However, the toxicity of Arecoline limits its application. Most current studies on its toxicity mainly focus on immunotoxicity, carcinogenesis, and cancer promotion. However, there are few systematic studies on its hepatotoxicity and mechanisms. Therefore, this research explored the mechanism of hepatotoxicity induced by Arecoline in rats and analyzed endogenous metabolite changes in rat plasma by combining network toxicology with metabolomics. The differential metabolites after Arecoline exposure, such as D-Lysine, N4-Acetylaminobutanal, and L-Arginine, were obtained by metabolomics study, and these differential metabolites were involved in the regulation of lipid metabolism, amino acid metabolism, and vitamin metabolism. Based on the strategy of network toxicology, Arecoline can affect the HIF-1 signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, and other concerning pathways by regulating critical targets, such as ALB, CASP3, EGFR, and MMP9. Integration of metabolomics and network toxicology results were further analyzed, and it was concluded that Arecoline may induce hepatotoxicity by mediating oxidative stress, inflammatory response, energy and lipid metabolism, and cell apoptosis.

Substance use and incidence of metabolic syndrome before midlife among military adults: the CHIEF cohort study

“…Betel nut contains several active ingredients such as arecoline, which has been revealed the adverse effects on glucose and lipid metabolism. Animal studies have revealed that arecoline can induce insulin resistance by impairing insulin signaling and glucose uptake in skeletal muscle cells ( 41 , 42 ). Arecoline can also stimulate the production of pro-inflammatory cytokines, such as TNF-α and IL-6, which are known to lead to insulin resistance and MetS ( 43 , 44 ).…”

Metabolomics in Preclinical Drug Safety Assessment: Current Status and Future Trends

“…Dioxin-exposed humans vs. control Distinct metabolite profiles 24 urinary steroid-related biomarkers [69] Tributyltin in zebrafish Affected steroid biosynthesis metabolism Diverse [70,71] 6-propyl-2-thiouracil in zebrafish (Neuro-) developmental toxicity methionine↓, tyrosine↑, pipecolic acid↑ and lysophosphatidylcholine↑ [72] Arecoline in rats ∆ lipid metabolism, amino acid metabolism, and vitamin metabolism ∆ D-Lysine, N4-Acetylaminobutanal, and L-Arginine [73]…”