Abstract
The root of Aconitum kusnezoffii (Caowu in Chinese, CW) is not only commonly used as a traditional Chinese medicine (TCM), but also served as a tonic in China. Due to its high toxicity, clinical poisoning cases induced by CW have frequently been reported. However, the mechanism is still unclear. In this study, Aconitum alkaloids and altered endogenous metabolites in CW poisoning patients were investigated to elucidate the possible intoxication mechanism. Eighteen alkaloids, including 6 toxic diester diterpenoid alkaloids (DDAs), were determined from the sera of patients. At the same time, 5-(diisopropylamino)amylamine (DIAAA) derivatization-ultrahigh performance liquid chromatography- quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF/MS) approach was applied in the metabolomics analysis to find much more carboxyl-containing metabolites (CCMs), which are the essential components for life and critical to elucidate the mechanism of toxicity. As a result, 32 altered metabolites after poisoning were identified. Among them, hydroxyeicosatetraenoic acids (HETEs) and some dicarboxylic acids were first found to be related to Aconitum alkaloids toxicity. Finally, biological pathway analysis indicated that the significantly changed metabolites were primarily involved in amino acid metabolism, TCA cycle, fatty acid metabolism, pyruvate metabolism, arachidonic acid metabolism, sphingolipid metabolism and so on. These results can not only provide more information on the mechanism of CW intoxication but also help the clinical diagnosis of CW poisoning.
Highlights
Aconitum species have been used as important sources for traditional Chinese medicine (TCM) in China for over 2000 years
DIAAA, O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxybenzotriazole hydrate (HOBt), triethylamine (TEA), and dimethyl sulfoxide (DMSO) (MS grade) were bought from Sigma-Aldrich Laboratories, Inc., MS-grade acetonitrile and methanol were purchased from Anaqua Chemicals Supply (Houston, TX, United States) and MS-grade formic acid was provided by SigmaAldrich Laboratories, Inc., Deionized water was supplied by a Millipore water purification system (Millipore, United States)
Aconitum alkaloids in the sera were detected and quantified using UHPLC-QQQ/MS
Summary
Aconitum species have been used as important sources for traditional Chinese medicine (TCM) in China for over 2000 years. The processed root of Aconitum kusnezoffii (Caowu in Chinese, CW) is commonly used to treat various diseases or deal with poor health conditions, such as syncope, rheumatic fever, painful joints, gastroenteritis, diarrhea, oedema, bronchial asthma, and some endocrine disorders (Liu et al, 2011). Due to its high toxicity and widespread usage, the poisoning cases induced by CW have frequently been reported in China (Singhuber et al, 2009; Liu et al, 2011; Li et al, 2016). There is still a lack of clinical information on metabolic regulation or specific biomarkers for the diagnosis of Aconitum toxic alkaloids poisoning
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