Applications Of NMR-Based Metabonomics On The Studies Of The Nephrotoxicity Of Aristolochia Manshuriensis

Chinese herbal medicine,a gem of the Chinese culture,has contributed to our life and health greatly.However,the tocxic side-effect and the security of Chinese herbs are more or less neglected.In recent years,the reports on the tocxicity of the Chinese herbs have been increased.Especially,the reports on some English and Belgian women who suffered from nephrotoxicity after taking Chinese herbs containing aristolochic acid A(AA) attracted international attention on the security of Chinese herbs,leading to the emergence of the word "Chinese herb nephropathy". The stem of Aristolochia manshuriensis Kom.,a commonly used Chinese herb named Guan Mu Tong containing AA as its main components,has renal toxicity which can results in serious nephropathy.In this thesis,NMR-based metabonomic techniques were established and applied to the study of the nephrotoxicity of Aristolochia manshuriensis Kom.1.The toxic effects of of the decoction of Aristolochia manshuriensis were investigated.The results showed clear dose and time dependence of the nephrotoxicity of Aristolochia manshuriensis,as revealed by the metabolic trajectories derived from the PCA results of urine samples from dosed rats.The levels of lactate,citrate,glucose,TMAO,taurine,succinate,2-oxoglutarate,methylamine, DMA,and DMG were markedly changed in plasma and urine samples from dosed rats compared to those from controls,suggesting the lesions in renal cortical tissues. The changes in these metabolites implied the disturbed glycolysis,TCA cycle, oxidative phosphorylation,and lipidβ-oxidation,the dysfunction of mitochondria.2.The toxic effects of of the decoction of Clematis armandii Franch.were investigated.The results showed that Clematis armandii caused no significant metabolicchanges in plasma and urine of rats,suggesting no observable toxic effects.3.Comparative studies of the toxicities of Aristolochia manshuriensis,Clematis armandii and aristolochic acid on rats were also carried out.The results indicate that aristolochic acid caused lesions in kidney to an extent similar to those by Aristolochia manshuriensis,as revealed by similar metabolic changes caused.The toxicity of aristolochic acid results in partial renal diffuse necrosis and inflammation in a dose-effect relationship.Aristolichic acid caused abnormal energy metabolism in rats. The changes in lactate,taurine,creatine,pyruvate and glucose can be used as potential markers of renal toxicity of Aristolochia manshuriensis and aristolochic acid for further investigation.4.In this study,the onset and development of the toxicity of Aristolochia manshuriensis were monitored by using metabonomic techniques,verified by the data of plasma biochemical analysis and histopathology.The above mentioned results indicate that metabonomics can monitor and describe the changes in metabolic phenotypes at different stages of toxicology,providing biological data for the researches of biomarkers.