title: Pulmonary toxicity and metabolic activation of dauricine in CD-1 mice.
abstract: 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.
authors.affiliation: Center for Developmental Therapeutics, Seattle Children's Research Institute, 1900 9th Ave., Seattle, WA 98101, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Jin
authors.forename: Jieyu
authors.initials: J
authors.lastname: Dai
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
authors.forename: Yansong
authors.initials: Y
authors.lastname: Gu
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D044182:Benzylisoquinolines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D001806:Blood Urea Nitrogen; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced; D011994:Recombinant Proteins / Q000737:chemistry; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D014018:Tissue Distribution
chemical_list: D044182:Benzylisoquinolines; D011994:Recombinant Proteins; D044005:Tetrahydroisoquinolines; C035934:dauricine; D003577:Cytochrome P-450 Enzyme System; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007654:Ketoconazole