ABSTRACT
About 15%-20% of drug-induced liver injury (DILI) will progress to chronic manifestation (CH-DILI), which sometimes advances rapidly to liver cirrhosis (LC-DILI) within 0.5-1 year with deteriorative clinical prognosis. Therefore, it is important to find a non-invasive diagnosis for early detection of liver cirrhosis. In this study, the metabolomic profiles revealed significant differences in the metabolites from the plasma of LC-DILI versus CH-DILI. We found 35 differential metabolites through principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Through pathway enrichment analysis, some up-regulated metabolic pathways reflected impaired liver functions such as bile acid, lipid synthesis and decomposition during cirrhosis. Five biomarkers were found to exhibit effective diagnosis value (AUC > 0.6), including phosphatidylcholine, lysoPC (18:1 (9Z)), creatine, taurochenodeoxycholic acid and taurocholic acid. Furthermore, we found that the relative content ratio between phosphatidylcholine and lysoPC (18:1 (9Z)) had a better distinguishing ability (AUC = 0.867). The relative content ratio also had the feature to reduce systematic errors of sample processing and instrument detection, therefore having a greater value for clinical application.
ABSTRACT
Focusing on the TCM-related adverse drug reactions, especially those conventionally non-toxic TCM induced hepatotoxicity, this paper has proposed and established the disease-syndrome-based toxicology evaluation pattern and approach for TCM, not only the normal rats, but the hepatic fibrosis model rat were studied hepatotoxic or hepatoprotective effects of rhubarb, meanwhile liver histopathology changes by histological tests such as HE and TUNEL staining. The metabolomics analysis method will be employed to screen the key metabolites and possible metabolic pathway of the dual effects of rhubarb in rats. The results showed that rhubarb could result in significant liver injury in normal rats, indicated by the elevation of plasma serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities (P L-arginine, creatine, L-valine, retinyl ester, and prostaglandin F2α were confirmed by multivariate statistical analysis and metabolic pathways enrichment analysis linked to six metabolic pathways, including taurine and hypotaurine metabolism, primary bile acid biosynthesis, arginine and proline metabolism, arachidonic acid metabolism, retinol metabolism and valine, leucine and isoleucine biosynthesis. In summary, the results suggested the dual effects of rhubarb screened by taurine and hypotaurine metabolism, primary bile acid biosynthesis and arginine and proline metabolism may be the key metabolic pathway related to You Gu Wu Yun phenomenon of rhubarb. This study will provide new vision and illustration of scientific evidences for the hepatotoxicity assessment and rational use of those drugs containing anthraquinones.