The Effect Of Metabolism Inhibition On The Hepatotoxicity And Nephrotoxicity Induced By The Active Components In Tripterygium Wilfordii

The traditional herbal medicine Tripterygium Wilfordii Hook. F. (TW) has been widely used for the treatment of rheumatoid arthritis in the clinic. It has also shown promising anti-inflammatory, antitumor and immunosuppressive activity. However, the clinical application of TW was greatly limited because of its narrow therapeutic window and its severe toxicity. Currently, several patented traditional medicine derived from Tripterygium wilfordii extracts are available. While the toxicity induced by metabolic interaction between the active components in Tripterygium wilfordii has not been studied. This study investigated the effect of metabolism inhibition on the hepatotoxicity and nephrotoxicity induced by the active components in Tripterygium wilfordii. Moreover, the potential hepatotoxicity and nephrotoxicity to mice after co-administeration of TP and other two traditional Chinese medicines were also investigated.1. The effect of metabolism on the hepatotoxicity and nephrotoxicity induced by the active components in Tripterygium wilfordiiTripterygium wilfordii contains several classes of active components, including terpenes, triterpenes and alkaloids. The effect of metabolism inhibition on the hepatotoxicity and nephrotoxicity of TW and its five major active components (triptonide, wiforgine, wilforine, euonine and peritassine A) in mice was evaluated.The toxicity of TW and five major active components was also evaluated in P450-inhibition and GSH-depleted mice model at two doses (the 20-fold and 120-fold of the therapeutic dose). The mortality of mice, serum biochemical parameters (ALT、 AST、BUN and CREA) and liver glutathione content were observed as the indicators for hepatotoxicity and nephrotoxicity. Metabolic pathways leading to potential detoxification of TW or its two representative components (triptonide and wilforgine) were evaluated in glutathione-depleted and CYP450s-inhibition mice.This study showed that neither triptonide nor alkaloids (wiforgine, wilforine, euonine and peritassine A) contributed to the acute toxicity of TW in combination with or without CYP inhibitor at dosage levels up to 120-fold of the therapeutic dose. TP was probably the main contributor to the toxicity of TW. 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-administeration with other CYP inhibitors or GSH-depleting agents. These results could provide guidance for clinical use of TW and structural modification of its analogues.2. The effect on the hepatotoxicity and nephrotoxicity induced by drug-combination with triptolideTripterygium wilfordii is frequently used in combination with other herbs, such as Glycyrrhiza uralensis Fisch (main component is glycyrrhizin) and Paeonia lactiflora Palls (main component is paeoniflorin). Based on the research of previous chapter (triptolide was probably the main toxicity component in TW), the hepatotoxicity and nephrotoxicity of TP combination with glycyrrhizin/paeoniflorin in mice was evaluated.The hepatotoxicity and nephrotoxicity of TP co-administeration with glycyrrhizin or paeoniflorin in mice were evaluated at three single or multiple doses (1-fold,20-fold and 100-fold of the therapeutic dose) treated with single dose or multidoses. The mortality of mice, serum biochemical levels (ALT、AST、BUN and CREA) and liver glutathione content were observed as indicators for hepatotoxicity and neprotoxicity.This study showed that there was no hepatotoxicity or nephrotoxicity for TP in combination with glycyrrhizin at dosage levels up to 20-fold of the therapeutic dose in mice treated for 28 days. A single dose (100-fold of the therapeutic dose) of glycyrrhizin cannot increase the toxicity of TP. Neither co-administeration with paeoniflorin at therapeutic dose nor 20-fold of the therapeutic dose showed toxicity in mice treated for 14 days. However, TP co-administered with paeoniflorin showed severe toxicity (including hepatotoxicity and nephrotoxicity) in mice treated for 28 days at 20-fold of the therapeutic dose. Caution should be taken for TW use in combination with paeoniflorin at a high dose especially for long time. A single dose (100-fold of the therapeutic dose) of paeoniflorin cannot increase the toxicity of TP. This result can provide guidance for clinical use of TP co-administered with glycyrrhizin or paeoniflorin.