Metabonomics Study Of Toxicity Induced By Melia Toosendan And Compatibility Research Of Toosendan Combined With RPA

Toosendan (Melia toosendan Sieb) is the mature fruit from Meliaceae Melia, named Chuan-lian-zi in China, with the function of circulate qi to relieve pain, kill parasites and treat tinea, was widely used for pectoralgia, coeliodynia, anti- botulismotoxin, etc. Toosendanin is the essential component from Chuan-lian-zi, the only anti- botulismotoxin found in natural compounds, inhibited a variety of tumor cell growth and induce apoptosis. The mechanism of toxicity induced by Chuan-lian-zi is still not clear, so it handicapped the clinical use. In this study, we employed NMR-based metabonomics approach to research the toxicity of decoction, different polarity solvent extracts, as well as combine with paeoniae radix alba(RPA) extract from Chuan-lian-zi. We interpreted the mechanisms of toxicity induced by Chuan-lian-zi and attenuate toxicity take advantage of compatibility from metabonomics aspect.The paper contains following parts:(A) A single oral dose (20 times of the clinical use) of decoction from Chuan-lian-zi was given to male SD rats. Observations of serum biomarkers, histopathology of liver and kidney, principle component analysis (PCA) of ~1H-NMR spectrum from rats'urine were executed. The results showed that Chuan-lian-zi could cause hepatotoxicity and nephrotoxicity. We selected 16 metabolites as toxicity biomarkers from PCA analysis, such as elevated levels of creatinine, creatine, TMAO, lactate, hippurate, betaine and glycine, decreaded levels of cirtrate, succinate and 2-OG.(B) Three different dosages (high, middle, low) of decoction from Chuan-lian-zi were given to rats during a successive period of 14-day, and a follow up 7-day for recovery. From the experiment, we obtained the results that the toxicity induced by Chuan-lian-zi has a relationship with time and dose. (C) Three different polarity solvent (petroleum ether, ethyl acetate, n-butanol) extracts from Toosendan were given to mouse, from body weight changes, biochemical indicators, histopathology observation and PCA analysis from serum, it concluded that the main toxic substance was in ethyl acetate site.(D) Compatibility research of Toosendan and RPA: It was found that two times RPA combined with Toosendan is the best proportion from preliminary experiment. Then the body weight changes, serum biochemical indicators, organ pathology observation and metabolites from urine were regarded as evaluate standards. The results showed that the damage of liver and kidney in T- RPA group was slighter than Toosendan group.The toxicity biomarkers were found, the relationship between time and dose effect was investigated, the main toxicity extract was ascertained and the compatibility theory was confirmed from the research. This thesis demonstrates the feasibility, reliability and superiority of metabonomics method in toosendan and compatibility research. The TCM theory was elaborated in modern science and technology, it might be benefit for TCM modernization and internationalization.