Center for Developmental Therapeutics, Seattle Children's Research Institute, 1900 9th Ave., Seattle, WA 98101, USA.
J Pharmacol Exp Ther. 2010 Mar;332(3):738-46. doi: 10.1124/jpet.109.162297. Epub 2009 Dec 11.
Dauricine is the major bioactive component isolated from the roots of Menispermum dauricum D.C. and has shown promising pharmacological activities with a great potential for clinic use. However, the adverse effects and toxicity of the alkaloid are unfortunately ignored. The objective of the current study was to evaluate the toxicity of dauricine in vitro and in vivo. Mice (CD-1) were treated intraperitoneally with dauricine at various doses, and sera and lung lavage fluids were collected after 24 h of treatment. No changes in serum aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen were noticed, whereas a dose-dependent increase in lactate dehydrogenase activity was observed in lung lavage fluids. Ethidium-based staining studies showed that remarkable cells lost membrane integrity in the lungs of the animals treated with dauricine at 150 mg/kg. Histopathological evaluation of lungs of mice showed that dauricine at the same dose caused significant alveolar edema and hemorrhage. Exposure to dauricine at 40 muM for 24 h resulted in up to 60% cell death in human lung cell lines BEAS-2B, WI-38, and A549. Ketoconazole showed protective effect on the pulmonary injury in mice given dauricine. A quinone methide metabolite of dauricine was identified in mouse lung microsomal incubations, and the presence of ketoconazole in the microsomal incubations suppressed the formation of the quinone methide metabolite. In conclusion, dauricine produced pulmonary injury in CD-1 mice. The pulmonary toxicity appears to depend on the metabolism of dauricine mediated by CYP3A. The electrophilic quinone methide metabolite probably plays an important role in the pulmonary toxicity induced by dauricine.
蝙蝠葛苏林碱是从北豆根中分离得到的主要生物活性成分，具有有前景的药理学活性，极有可能应用于临床。然而，该生物碱的不良反应和毒性却被忽视了。本研究旨在评估蝙蝠葛苏林碱的体内和体外毒性。用不同剂量的蝙蝠葛苏林碱腹腔注射 CD-1 小鼠，处理 24 h 后收集血清和肺灌洗液。血清中天冬氨酸转氨酶、丙氨酸转氨酶和血尿素氮没有变化，而肺灌洗液中乳酸脱氢酶活性呈剂量依赖性增加。基于溴乙锭的染色研究表明，在 150 mg/kg 剂量的蝙蝠葛苏林碱处理的动物肺部，明显有细胞失去膜完整性。对小鼠肺部的组织病理学评估表明，相同剂量的蝙蝠葛苏林碱导致显著的肺泡水肿和出血。暴露于 40 μM 蝙蝠葛苏林碱 24 h 导致人肺细胞系 BEAS-2B、WI-38 和 A549 的细胞死亡高达 60%。酮康唑对给予蝙蝠葛苏林碱的小鼠的肺部损伤具有保护作用。在小鼠肺微粒体孵育中鉴定出蝙蝠葛苏林碱的醌甲基化物代谢物，酮康唑在微粒体孵育中的存在抑制了醌甲基化物代谢物的形成。总之，蝙蝠葛苏林碱在 CD-1 小鼠中产生了肺部损伤。这种肺部毒性似乎依赖于 CYP3A 介导的蝙蝠葛苏林碱代谢。亲电的醌甲基化物代谢物可能在蝙蝠葛苏林碱诱导的肺部毒性中发挥重要作用。
