title: Investigation of the active components in Tripterygium wilfordii leading to its acute hepatotoxicty and nephrotoxicity.
abstract: BACKGROUND
  The traditional herbal medicine Tripterygium wilfordii Hook. f. (TW) has been widely used for the treatment of rheumatoid arthritis and autoimmune disease in the clinic. However, adverse reactions of TW including hepatotoxicity and nephrotoxicity have been frequently reported. Terpenes and alkaloids are among the most important active components in TW. Triptolide (TP), a major terpene in TW, has been found to induce toxicity, and metabolic pathways could lead to detoxification of TP. In this study, whether other major terpenes or alkaloids in TW contribute to its toxicity was investigated. The role of metabolic eliminations in their potential detoxification process was also evaluated.
  
  
  METHODS
  The toxicity of TW and its five major active components (one terpene and four alkaloids) in mice was evaluated in terms of mortality and blood biochemical levels (ALT, AST, BUN and CREA). TP was used as a positive control. Metabolic pathways leading to potential detoxification of TW or its two representative components (triptonide and wilforgine) were evaluated in glutathione (GSH)-depleted (treated with L-buthionine-S,R-sulfoxinine, BSO) and aminobenzotriazole (ABT; a nonspecific inhibitor for P450s)-treated mice.
  
  
  RESULTS
  In normal mice, the major metabolic pathways for the terpene compounds TP and triptonide (TN) were hydroxylation and cysteine conjugation, and the alkaloid wilforgine (WG) mainly underwent oxidative metabolism and hydrolysis. In ABT/BSO-treated mice, the hydroxylated metabolites of TP, TN and WG were found at a lower level than normal mice, and the level of cysteine conjugates of TN increased probably due to the stress response. Compared with normal mice, mortality and levels of ALT (but not BUN) were significantly higher (P<0.01) in TW (or TP)-treated mice (1.2 mg kg(-1)), indicating the acute toxicity (may not nephrotoxicity) of TW and its active component TP. Pretreatment with ABT and/or BSO increased the acute toxicity (including hepatotoxicity and nephrotoxicity) caused by TW or TP. No significant toxicity was found for TN or four alkaloids in normal mice or ABT/BSO-treated mice.
  
  
  CONCLUSIONS
  TP was probably the main contributor to the toxicity of TW, and the terpene TN and alkaloids in TW may be of no toxicological concern at dosage levels up to 20-fold of the therapeutic dose. Metabolic eliminations to less reactive metabolites implied a high potential for detoxification of TW, and caution should be taken for TW clinical use during co-administration with other CYP inhibitors or GSH-depleting agents.
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Xin-Xiu
authors.initials: XX
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Fu-Ying
authors.initials: FY
authors.lastname: Du
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Hui-Xiang
authors.initials: HX
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China.
authors.forename: Jian-Bo
authors.initials: JB
authors.lastname: Ji
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, China. Electronic address: xingjie@sdu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Xing
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D005978:Glutathione / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced*; D051379:Mice; D015394:Molecular Structure; D010936:Plant Extracts / Q000737:chemistry / Q000633:toxicity*; D029757:Tripterygium / Q000737:chemistry*
chemical_list: D010936:Plant Extracts; D005978:Glutathione
keywords: Active components; Hematology; Metabolism; Toxicity; Tripterygium wilfordii