BACKGROUND: metabolic consequences remain poorly defined. PURPOSE: toxicity evaluation, and liver metabolomics. METHODS: Network toxicology and molecular docking were used to prioritize hepatotoxic PAs and their putative targets. LC-MS/MS fingerprints of major PAs in SBH sourced from twelve regions were established. A spectrum-toxicity correlation model combining grey relational analysis and OPLS regression was applied to assess associations between PAs abundance and hepatotoxicity in mice. Untargeted metabolomics further delineated hepatic metabolic perturbations induced by seneciphylline (SPL). RESULTS: SPL, senecionine, adonifoline, and senkirkine were prioritized as candidate hepatotoxic PAs, with CYP3A4/CYP2C9 and DNA adduct-related pathways highlighted as potentially relevant toxicological nodes. Considerable regional variation in PAs levels was observed across SBH samples. Acute SBH exposure caused marked liver injury, and spectrum-toxicity modeling indicated that SPL showed the strongest association with hepatotoxicity among the detected PAs. Metabolomic profiling further showed that SPL exposure was associated with substantial alterations in lipid and bile acid metabolism, glutathione metabolism, and the pentose phosphate pathway, together with enrichment of xenobiotic metabolism by cytochrome P450 and chemical carcinogenesis-DNA adduct pathways. CONCLUSION: SPL is closely associated with SBH-induced hepatotoxicity and produces a metabolic signature consistent with canonical PAs bioactivation. Although SPL appears to be the most influential PAs among those detected, definitive comparisons of toxic potency require further validation using equimolar pure-compound exposure models.
Yang et al. (Wed,) studied this question.