Fuying Du and Zhaohua Liu contributed equally to this paper.
Metabolic pathways leading to detoxification of triptolide, a major active component of the herbal medicine Tripterygium wilfordii
Article first published online: 9 JUL 2013
Copyright © 2013 John Wiley & Sons, Ltd.
Journal of Applied Toxicology
Volume 34, Issue 8, pages 878–884, August 2014
How to Cite
Du, F., Liu, Z., Li, X. and Xing, J. (2014), Metabolic pathways leading to detoxification of triptolide, a major active component of the herbal medicine Tripterygium wilfordii. J. Appl. Toxicol., 34: 878–884. doi: 10.1002/jat.2906
- Issue published online: 25 JUN 2014
- Article first published online: 9 JUL 2013
- Manuscript Accepted: 28 MAY 2013
- Manuscript Revised: 9 MAY 2013
- Manuscript Received: 11 APR 2013
- National Natural Science Foundation of China. Grant Number: 30901829
- Shandong Natural Science Foundation of China. Grant Number: BS2009SW013
- conjugated metabolites;
- GSH-depleted mice
Triptolide (TP) shows promising anti-inflammatory and antitumor activity but with severe toxicity. TP is a natural reactive electrophile containing three epoxide groups, which are usually linked to hepatotoxicity via their ability to covalently bind to cellular macromolecules. In this study, metabolic pathways leading to detoxification of TP were evaluated in glutathione (GSH)-depleted (treated with L-buthionine-S,R-sulfoxinine, BSO) and aminobenzotriazole (ABT; a non-specific inhibitor for P450s)-treated mice. The toxicity of TP in mice was evaluated in terms of mortality and levels of serum alanine transaminase (ALT). In incubates with NADPH- and GSH-supplemented liver microsomes, seven GSH conjugates derived from TP were detected. In mice, these hydrolytically unstable GSH conjugates underwent γ-glutamyltranspeptidase/dipeptidases-mediated hydrolysis leading to two major cysteinylglycine conjugates, which underwent further hydrolysis by dipeptidases to form two cysteine conjugates of TP. In ABT-treated mice, the hydroxylated metabolites of TP were found at a lower level than normal mice, and their subsequent conjugated metabolites were not found. The level of cysteinylglycine and cysteine conjugates derived from NADPH-independent metabolism increased in mice treated with both TP and BSO (or ABT), which could be the stress response to toxicity of TP. Compared with normal mice, mortality and ALT levels were significantly higher in TP-treated mice, indicating the toxicity of TP. Pretreatment of ABT increased the toxicity caused by TP, whereas the mortality decreased in GSH-depleted mice. Metabolism by cytochrome P450 enzymes to less reactive metabolites implied a high potential for detoxification of TP. The GSH conjugation pathway also contributed to TP's detoxification in mice. Copyright © 2013 John Wiley & Sons, Ltd.