Investigation of Liver Injury of Polygonum multiflorum Thunb. in Rats by Metabolomics and Traditional Approaches

Abstract

Liver injury induced by Polygonum multiflorum Thunb. (PM) have been reported since 2006, which aroused widespread concern. However, the toxicity mechanism of PM liver injury remained unclear. In this study, the mechanism of liver injury induced by different doses of PM after long-term administration was investigated in rats by metabolomics and traditional approaches. Rats were randomly divided into control group and PM groups. PM groups were oral administered PM of low (10 g/kg), medium (20 g/kg), high (40 g/kg) dose, while control group was administered distilled water. After 28 days of continuous administration, the serum biochemical indexes in the control and three PM groups were measured and the liver histopathology were analyzed. Also, UPLC-Q-TOF-MS with untargeted metabolomics was performed to identify the possible metabolites and pathway of liver injury caused by PM. Compared with the control group, the serum levels of ALT, AST, ALP, TG, and TBA in middle and high dose PM groups were significantly increased. And the serum contents of T-Bil, D-Bil, TC, TP were significantly decreased. However, there was no significant difference between the low dose group of PM and the control group except serum AST, TG, T-Bil, and D-Bil. Nine biomarkers were identified based on biomarkers analysis. And the pathway analysis indicated that fat metabolism, amino acid metabolism and bile acid metabolism were involved in PM liver injury. Based on the biomarker pathway analysis, PM changed the lipid metabolism, amino acid metabolism and bile acid metabolism and excretion in a dose-dependent manner which was related to the mechanism of liver injury.

Acute Bone Damage Through Liver-bone Axis Induced by Thioacetamide in Rats

“…In this study, the increased concentration of AST and ALT represented severe liver injury, in addition, the increased concentration of UA, UREA, CREA, and TBA represented severe kidney injury, which correlates with other studies (Al-Hashem et al 2019; Jeong et al 2015; Waters et al 2005). We also found the decreased concentration of TP and increased concentration of ALP, which indicated liver disease (Li et al 2017). The levels of rat serum ALT, AST, and ALP exposed to 200 mg/Kg TAA and 400 mg/Kg TAA group were signi cantly increased, which indicated that the liver cell membrane was impaired and the release of them into blood was increased after TAA administration.…”

HLA‐B*35:01 Allele Is a Potential Biomarker for Predicting Polygonum multiflorum–Induced Liver Injury in Humans

“…Unfortunately, no satisfactory biomarkers are currently available to identify human populations susceptible to this injury. Moreover, conventional animal models in which only high doses that significantly exceed the typical PM dose that can induce liver injury are not suitable for mimicking dose‐independent, PM‐induced idiosyncratic hepatotoxicity. Recently, however, a rat model of immune action–mediated liver injury induced by cotreatment with a nontoxic dose of lipopolysaccharide and a therapeutic dose of PM exhibited liver injury characteristics similar to those shown in humans and induced a state of immune activation and inflammatory stress .…”

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

“…Liver injury caused by green tea extracts shows dose dependent features but diagnostic biomarkers were not described [67]. Dose dependency can be assumed for HILI caused by phytochemicals derived from germander (Teucrium chamaedris) [17,[75][76][77][78][79], Polygonum multiflorum [68,69,80,81], and plants containing unsaturated pyrrolizidine alkaloids (PAs) [15,[82][83][84][85][86][87][88][89][90]. For these herbs, diagnostic biomarkers are known and in clinical use although test validation was rarely provided [17].…”

“…In experimental liver injury by Polygonum multiflorum, nine biomarkers were identified using a pathway analysis, which indicated some metabolic involvement of pathways related to lipids, amino acids, and bile acids, but this was not evaluated in patients with liver injury [81]. In clinical studies using prospectively RUCAM for causality assessment in patients with HILI caused by Polygonum multiflorum, a sophisticated but complex evidence chain-based causality identification algorithm was used that also included metabolomics analyses [68].…”

“…Although most HILI cases have correctly been evaluated for causality, listings contained in databases or scientific publications would be greatly improved if all HILI cases, as well as all DILI cases, received prior evaluation using RUCAM or biomarkers. Some examples are referenced including earlier reports from our group [16,35,62,[80][81][82][83][84][85][86][87][88][89][90][91][92][93][94].…”