Abstract
“RenqingMangjue” pill (RMP), as an effective prescription of Traditional Tibetan Medicine (TTM), has been widely used in treating digestive diseases and ulcerative colitis for over a thousand years. In certain classical Tibetan Medicine, heavy metal may add as an active ingredient, but it may cause contamination unintentionally in some cases. Therefore, the toxicity and adverse effects of TTM became to draw public attention. In this study, 48 male Wistar rats were orally administrated with different dosages of RMP once a day for 15 consecutive days, then half of the rats were euthanized on the 15th day and the remaining were euthanized on the 30th day. Plasma, kidney and liver samples were acquired to 1H NMR metabolomics analysis. Histopathology and ICP-MS were applied to support the metabolomics findings. The metabolic signature of plasma from RMP-administrated rats exhibited increasing levels of glucose, betaine, and creatine, together with decreasing levels of lipids, 3-hydroxybutate, pyruvate, citrate, valine, leucine, isoleucine, glutamate, and glutamine. The metabolomics analysis results of liver showed that after RMP administration, the concentrations of valine, leucine, proline, tyrosine, and tryptophan elevated, while glucose, sarcosine and 3-hydroxybutyrate decreased. The levels of metabolites in kidney, such as, leucine, valine, isoleucine and tyrosine, were increased, while taurine, glutamate, and glutamine decreased. The study provides several potential biomarkers for the toxicity mechanism research of RMP and shows that RMP may cause injury in kidney and liver and disturbance of several pathways, such as energy metabolism, oxidative stress, glucose and amino acids metabolism.
Highlights
Toxicological Effects of “Renqing Mangjue” Pill popularity of Asian traditional medicine, concerns over the heavy metal presence aroused, whether it was added as ingredients, or caused contamination unintentionally (Aslam et al, 1979; KangYum and Oransky, 1992; Hardy et al, 1995; Ernst, 2002; Saper et al, 2004)
Rats were randomly allocated into four groups (n = 12) as following: low dose group (LD), middle dose group (MD), and high dose group (HD), which were administrated with RMP at a dose of 83.33, 333.33, and 1333.33 respectively, and control group (NC) was treated with approximately equal volume of 0.9% saline solution
Representative 600 MHz 1H Nuclear magnetic resonance (NMR) spectra of plasma and tissue extracts obtained from control and HD on 15th days were showed in Figure 2, with major metabolites in the integrated regions assigned
Summary
Toxicological Effects of “Renqing Mangjue” Pill popularity of Asian traditional medicine, concerns over the heavy metal presence aroused, whether it was added as ingredients, or caused contamination unintentionally (Aslam et al, 1979; KangYum and Oransky, 1992; Hardy et al, 1995; Ernst, 2002; Saper et al, 2004). Metabolomics provides an important method to trace the metabolic global changes in the biological processes in biofluids (e.g., blood and urine) or tissues (e.g., liver and kidney) of an organism (Nicholson et al, 2002; Xuan et al, 2011). Coupled plasma mass spectrometry (ICP-MS), with the advantages of rapid and low detection limit, multi element analysis, and wide linear dynamic range, is considered as one of the most sensitive device for the determination of metal element in the biologic samples (Sarmiento-González et al, 2008). 1H NMR-based metabolomics approach is employed to investigate the changes of metabolic profiles occurring in the plasma and tissues for the rat induced by different dosages of RMP. ICP-MS was applied to determine the concentrations of heavy metals in plasma, liver and kidney tissue extracts. It is hoped that the study will offer several potential toxicity information of RMP
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