In vitro Metabolism of Humantenine in Liver Microsomes from Human, Pig, Goat and Rat

Abstract

Background: Gelsemium elegans Benth（G. elegans） is a well-known toxic plant. Alkaloids are main active components of G. elegans. Currently, the metabolism of several alkaloids, such as gelsenicine, koumine, and gelsemine, has been widely studied. However, as one of the most important alkaloids in G. elegans, the metabolism of humantenine has not been studied yet. Methods: In order to elaborate on the in vitro metabolism of humantenine, a comparative analysis of its metabolic profile in human, pig, goat and rat liver microsomes was carried out using high-performance chromatography/quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS) for the first time. Results: Totally, ten metabolites of humantenine were identified in liver microsomes from human (HLMs), pig (PLMs), goat (GLMs) and rat (RLMs) based on the accurate MS/MS spectra. Five metabolic pathways of humantenine, including demethylation, dehydrogenation, oxidation, dehydrogenation and oxidation, and demethylation and oxidation, were proposed in this study. There were qualitative and quantitative species differences in the metabolism of humantenine among the four species. Conclusions: The in vitro metabolism of humantenine in HLMs, PLMs, GLMs and RLMs was studied by a sensitive and specific detection method based on HPLC/QqTOF-MS. The results indicated that there were species-related differences in the metabolism of humantenine. This work might be of great significance for the further research and explanation of species differences in terms of toxicological effects of G. elegans.

A high‐resolution mass spectrometric approach to a qualitative and quantitative comparative metabolism of the humantenine‐type alkaloid rankinidine

“…Rankinidine is a humantenine‐type alkaloid, and oxidation, demethylation and reduction are also its major metabolic pathways. Thus, the metabolic pathways of Gelsemium alkaloids are similar between species 10 . It has been shown that CYP450 enzymes affect alkaloid metabolism by mediating capacity of bioactivation 23 .…”

“…Our team studied the metabolism of gelsenicine, 19 koumine, 20 gelsemine 24 and humantenine 10 and found that demethylation, oxidation and reduction were their important metabolic reactions. Rankinidine is a humantenine‐type alkaloid, and oxidation, demethylation and reduction are also its major metabolic pathways.…”

“…Thus, the metabolic pathways of Gelsemium alkaloids are similar between species. 10 It has been shown that CYP450 enzymes affect alkaloid metabolism by mediating capacity of bioactivation. 23 The species-specific isoforms of CYP3A show obvious differences among species in catalytic activity.…”

“…Moreover, the toxicological or pharmacological effects of Gelsemium in different species are quite different. While Gelsemium appears highly toxic to rats and humans, it has also been demonstrated to have a role in promoting animal growth in pigs and goats 10 . Therefore, it is important to study the metabolism of Gelsemium among different species in terms of its food safety and toxicity interpretation in animals.…”