In Vitro and in Vivo Studies of the Metabolic Activation of 8-Epidiosbulbin E Acetate

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• 作者：Dongju Lin ; Xiucai Guo ; Huiyuan Gao ; Li Cheng ; Maosheng Cheng ; Shaojiang Song ; Ying Peng ; Jiang Zheng
• 刊名：Chemical Research in Toxicology
• 出版年：2015
• 出版时间：September 21, 2015
• 年：2015
• 卷：28
• 期：9
• 页码：1737-1746
• 全文大小：555K
• ISSN：1520-5010

文摘

Furanoid 8-epidiosbulbin E acetate (EEA) is a major constituent of herbal medicine Dioscorea bulbifera L. (DB), a traditional Chinese medicine herb. Our preliminary studies demonstrated that administration of EEA caused acute hepatotoxicity in mice, and the observed toxicity required cytochromes P450-mediated metabolism. Metabolic activation studies of EEA were performed in vitro and in vivo. Microsomal incubations of EEA supplemented with N-acetyl lysine (NAL) and glutathione (GSH) generated six metabolites (M1鈥揗6). M1鈥揗4 were characterized as pyrrole derivatives, and M5 and M6 were pyrrolinones. M2鈥揗6 were detected in bile and/or urine of rats given EEA. Dimethyldioxirane-mediated oxidation of EEA in the presence of NAL and GSH produced M1鈥揗6, all of which were generated in microsomal incubations. The structures of M3 and M6 were confirmed by ¹H and ¹³C NMR. These findings provide evidence for the metabolic activation of EEA to the corresponding cis-enedial intermediate both in vitro and in vivo. Ketoconazole inhibited the microsomal production of the cis-enedial, and P450 3A4 was found to be the primary enzyme involved in the bioactivation of EEA.