Pulmonary Toxicity and Metabolic Activation of Dauricine in CD-1 Mice

doi:10.1124/jpet.109.162297

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	Pulmonary Toxicity and Metabolic Activation of Dauricine in CD-1 Mice
	Jin, Hua 2; Dai, Jieyu 2; Chen, Xiaoyan1 ; Liu, Jia1 ; Zhong, Dafang1 ; Gu, Yansong 3; Zheng, Jiang 2
刊名	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
	2010-03
卷号	332 期号:3 页码:738-746
ISSN号	0022-3565
DOI	10.1124/jpet.109.162297
文献子类	Article
英文摘要	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 mu M 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.
资助项目	National Natural Science Foundation of China[30873119]
WOS关键词	QUINONE METHIDE METABOLITES ; HUMAN LIVER-MICROSOMES ; MURINE CLARA CELLS ; BISBENZYLISOQUINOLINE ALKALOIDS ; DNA-ADDUCTS ; HUMAN LUNG ; IDENTIFICATION ; RAT ; CYTOTOXICITY ; SPECTROMETRY
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000274800200006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278969]
专题	上海药物代谢研究中心
通讯作者	Zheng, Jiang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China; 2.Univ Washington, Ctr Dev Therapeut, Div Gastroenterol, Seattle Childrens Res Inst,Dept Pediat, Seattle, WA 98101 USA; 3.Univ Washington, Div Radiobiol, Dept Radiat Oncol, Seattle, WA 98101 USA
推荐引用方式 GB/T 7714	Jin, Hua,Dai, Jieyu,Chen, Xiaoyan,et al. Pulmonary Toxicity and Metabolic Activation of Dauricine in CD-1 Mice[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2010,332(3):738-746.
APA	Jin, Hua.,Dai, Jieyu.,Chen, Xiaoyan.,Liu, Jia.,Zhong, Dafang.,...&Zheng, Jiang.(2010).Pulmonary Toxicity and Metabolic Activation of Dauricine in CD-1 Mice.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,332(3),738-746.
MLA	Jin, Hua,et al."Pulmonary Toxicity and Metabolic Activation of Dauricine in CD-1 Mice".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 332.3(2010):738-746.