Comparative metabolism of gelsenicine in liver microsomes from humans, pigs, goats and rats

Rationale Gelsemium elegans(G. elegans) is highly toxic to humans and rats but has insecticidal and growth-promoting effects on pigs and goats. However, the mechanisms behind the toxicity differences ofG. elegansare unclear. Gelsenicine, isolated fromG. elegans,has been reported to be a toxic alkaloid. Methods In this study, thein vitrometabolism of gelsenicine was investigated and compared for the first time using human (HLM), pig (PLM), goat (GLM) and rat (RLM) liver microsomes and high-performance liquid chromatography/mass spectrometry (HPLC/MS). Results In total, eight metabolites (M1-M8) were identified by using high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (HPLC/QqTOF-MS). Two main metabolic pathways were found in the liver microsomes of the four species: demethylation at the methoxy group on the indole nitrogen (M1) and oxidation at different positions (M2-M8).M8was identified only in the GLM. The degradation ratio of gelsenicine and the relative percentage of metabolites produced during metabolism were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/QqQ-MS/MS). The degradation ratio of gelsenicine in liver microsomes decreased in the following order: PLM >= GLM > HLM > RLM. The production ofM1decreased in the order of GLM > PLM > RLM > HLM, the production ofM2was similar among the four species, and the production ofM3was higher in the HLM than in the liver microsomes of the other three species. Conclusions Based on these results, demethylation was speculated to be the main gelsenicine detoxification pathway, providing vital information to better understand the metabolism and toxicity differences ofG. elegansamong different species.