State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health , Macau University of Science and Technology , Avenida Wai Long , Taipa , Macao 999078 , Special Administrative Region of the People's Republic of China.
International Institute for Translational Chinese Medicine , Guangzhou University of Chinese Medicine , Guangzhou 510006 , People's Republic of China.
J Nat Prod. 2019 Apr 26;82(4):980-989. doi: 10.1021/acs.jnatprod.8b01039. Epub 2019 Mar 20.
Aconitum carmichaelii is a traditional Chinese herbal medicine used for the treatment of pain and inflammation in the joints. However, the strong cardiotoxicity hinders its use. Although diester- and monoester-type diterpenoids, e.g., aconitine, mesaconitine, and hypacaonitine, are commonly considered as the toxic components, the toxicity of A. carmichaelii cannot be completely explained by the compounds reported. To investigate further the cardiotoxic compounds and their potential mechanism, the chemical constituents were first isolated by column chromatography and identified using mass spectrometry and NMR spectroscopy. Two new hetisine-type (1 and 2) and four new aconitine-type alkaloids (3-6) were assigned. The cardiac cytotoxicity assessed on H9c2 cells indicated that the new compound 4 as well as six known alkaloids (7 and 9-13) exhibited significant toxicities. A preliminary structure-toxicity relationship study suggested that substitution at C-8 and C-10 both have a significant influence on cardiotoxicity, and such toxicity decreased in the order OBz-8, OBu-8, and OMe-8. The presence of an OH-10 group abolished the toxicity. Finally, it was found that ion channel disorder and induction of mitochondrial-mediated cell apoptosis are the possible mechanisms of cardiotoxicity among the compounds studied.
乌头是一种传统的中药，用于治疗关节疼痛和炎症。然而，其强烈的心脏毒性阻碍了它的应用。虽然二酯型和单酯型二萜生物碱，如乌头碱、次乌头碱和新乌头碱，通常被认为是有毒成分，但乌头的毒性不能完全用已报道的化合物来解释。为了进一步研究其心脏毒性化合物及其潜在机制，首先采用柱层析法分离化学成分，并通过质谱和 NMR 光谱鉴定。鉴定出两种新的次乌头碱型（1 和 2）和四种新的乌头碱型生物碱（3-6）。在 H9c2 细胞上评估心脏细胞毒性表明，新化合物 4 以及六种已知生物碱（7 和 9-13）表现出显著的毒性。初步的结构-毒性关系研究表明，C-8 和 C-10 取代均对心脏毒性有显著影响，其毒性顺序为 OBz-8、OBu-8 和 OMe-8。而 10-OH 基团的存在则消除了毒性。最后发现，化合物引起的离子通道紊乱和线粒体介导的细胞凋亡可能是其心脏毒性的机制。
