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Pulmonary toxicity and metabolic activation of tetrandrine in CD-1 mice
Authors:Jin Hua  Li Liang  Zhong Dafang  Liu Jia  Chen Xiaoyan  Zheng Jiang
Affiliation:Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington, Seattle, Washington 98101, USA.
Abstract:Tetrandrine, a bisbenzylisoquinoline alkaloid, has demonstrated promising pharmacologic activities. The alkaloid has a great potential for clinical use, so a careful, thorough toxicity evaluation of the alkaloid is required. In the present study, 24 h acute toxicity of tetrandrine was evaluated in CD-1 mice. Single intraperitoneal doses of tetrandrine at 150 mg (0.24 mmol)/kg were found to cause alveolar hemorrhage and over 3-fold elevation of lactate dehydrogenase activity in bronchoalveolar lavage fluids. Ethidium-based staining showed loss of membrane integrity in significant numbers of cells in the lungs of the animals treated with the same doses of tetrandrine. As much as 60% reduction in cell viability was observed after 24 h of exposure to tetrandrine at 40 μM in human lung cell lines NL-20 and WI-38. Ketoconazole, an inhibitor of P450 3A, showed a protective effect on the pulmonary injury in mice given tetrandrine. A glutathione (GSH) conjugate derived from O-demethylated tetrandrine was detected in incubations of tetrandrine with NADPH- and GSH-supplemented human liver and mouse lung microsomes. The electrophilic metabolite trapped by GSH is considered to be a quinone methide derivative. The formation of the metabolite reactive to GSH was found to require the presence of NADPH. The coincubation of ketoconazole suppressed the generation of the GSH conjugate. Tetrandrine was incubated with a selection of recombinant human cytochrome P450 enzymes, and only P450s 3A4 and 3A5 were responsible for the production of the reactive metabolite. The results implicate a possible correlation between the formation of the quinone methide metabolite of tetrandrine and the pulmonary toxicity induced by tetrandrine.
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