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UPLC/MS/MS-Based Metabolomics Study of the Hepatotoxicity and Nephrotoxicity in Rats Induced by Polygonum multiflorum Thunb.

ABSTRACT: Polygonum multiflorum Thunb. (PM) is one of the most frequently used natural products in China. Its hepatotoxicity has been proven and reported. However, chronic PM toxicity is a dynamic process, and a few studies have reported the long-term hepatotoxic mechanism of PM or its nephrotoxicity. To elucidate the mechanism of hepatotoxicity and nephrotoxicity induced by PM after different administration times, different samples from rats were systematically investigated by traditional biochemical analysis, histopathological observation, and nontargeted metabolomics. The concentrations of direct bilirubin (DBIL) at 4 weeks and total bile acid, DBIL, uric acid, and blood urea nitrogen at 8 weeks were significantly increased in the treatment group compared with those in the control group. Approximately, 12 metabolites and 24 proteins were considered as unique toxic biomarkers and targets. Metabolic pathway analysis showed that the primary pathways disrupted by PM were phenylalanine and tyrosine metabolism, which resulted in liver injury, accompanied by chronic kidney injury. As the administration time increased, the toxicity of PM gradually affected vitamin B6, bile acid, and bilirubin metabolism, leading to aggravated liver injury, abnormal biochemical indicators, and marked nephrotoxicity. Our results suggest that the hepatotoxicity and nephrotoxicity caused by PM are both dynamic processes that affect different metabolic pathways at different administration times, which indicated that PM-induced liver and kidney injury should be treated differently in the clinic according to the degree of injury.

SUBMITTER: Yan Y

PROVIDER: S-EPMC7227050 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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UPLC/MS/MS-Based Metabolomics Study of the Hepatotoxicity and Nephrotoxicity in Rats Induced by <i>Polygonum multiflorum</i> Thunb.

Yan Yan Y Shi Ning N Han Xuyang X Li Guodong G Wen Binyu B Gao Jian J

ACS omega 20200428 18

<i>Polygonum multiflorum</i> Thunb. (PM) is one of the most frequently used natural products in China. Its hepatotoxicity has been proven and reported. However, chronic PM toxicity is a dynamic process, and a few studies have reported the long-term hepatotoxic mechanism of PM or its nephrotoxicity. To elucidate the mechanism of hepatotoxicity and nephrotoxicity induced by PM after different administration times, different samples from rats were systematically investigated by traditional biochemi ...[more]

PMID: 32426606

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Project description:BackgroundThe idiosyncratic hepatotoxicity of Polygonum multiflorum (PM) has attracted considerable interest, but the idiosyncratically hepatotoxic components and endogenous metabolite changes resulting from idiosyncratic hepatotoxicity of PM are not well understood. The aim of this study was to identify the idiosyncratically hepatotoxic components and potential endogenous metabolic biomarkers for PM-induced liver injury.MethodsSerum biochemical indicators and hematoxylin and eosin (H&E) staining were evaluated to identify pathological changes. Gas chromatography/mass spectrometry (GC-MS) was performed to identify changes in metabolic biomarkers. Orthogonal projection to latent structures discriminant analysis (OPLS-DA) was applied to determine group clustering trends and differential metabolites.ResultsThe results for the liver index, the liver function index and liver pathology showed that Polygonum multiflorum ethanol extract (PME), 50% ethanol elution fractions and tetrahydroxystilbene glucoside (TSG) from PME can induce idiosyncratic hepatotoxicity. TSG was the main idiosyncratically hepatotoxic component. Forty endogenous metabolites were identified in the rat liver. Six biomarkers, including lower levels of L-valine and higher levels of 3-hydroxybutyric acid, hexadecanoic acid, ribose, phosphoric acid and oxalic acid, were related to PM-induced liver injury. These differential biomarkers led to disruptions in amino acid, fatty acid, oxalate, energy and glucose metabolism. A total of 32 types of endogenous metabolites were identified in rat serum. Ten biomarkers were related to the liver injury induced by TSG, including lower levels of L-valine and L-proline and higher levels of urea, caproic acid, DL-malic acid, D-mannose, 3-hydroxybutyric acid, D-galactose, octadecane and hexadecanoic acid. These differential biomarkers led to disruptions in amino acid, glucose and fat metabolism. The mechanism of idiosyncratic hepatotoxicity in PM involves TSG-induced disruptions in amino acid metabolism, lipid metabolism, energy metabolism and glucose metabolism.ConclusionsThese findings reflect the material basis and metabolic mechanism of idiosyncratic PM hepatotoxicity.

Project description:An increasing number of cases of herb-induced liver injury (HILI) have been reported, presenting new clinical challenges. In this study, taking Polygonum multiflorum Thunb (PmT) as an example, we proposed a computational systems toxicology approach to explore the molecular mechanisms of HILI. First, the chemical components of PmT were extracted from 3 main TCM databases as well as the literature related to natural products. Then, the known targets were collected through data integration, and the potential compound-target interactions (CTIs) were predicted using our substructure-drug-target network-based inference (SDTNBI) method. After screening for hepatotoxicity-related genes by assessing the symptoms of HILI, a compound-target interaction network was constructed. A scoring function, namely, Ascore, was developed to estimate the toxicity of chemicals in the liver. We conducted network analysis to determine the possible mechanisms of the biphasic effects using the analysis tools, including BiNGO, pathway enrichment, organ distribution analysis and predictions of interactions with CYP450 enzymes. Among the chemical components of PmT, 54 components with good intestinal absorption were used for analysis, and 2939 CTIs were obtained. After analyzing the mRNA expression data in the BioGPS database, 1599 CTIs and 125 targets related to liver diseases were identified. In the top 15 compounds, seven with Ascore values >3000 (emodin, quercetin, apigenin, resveratrol, gallic acid, kaempferol and luteolin) were obviously associated with hepatotoxicity. The results from the pathway enrichment analysis suggest that multiple interactions between apoptosis and metabolism may underlie PmT-induced liver injury. Many of the pathways have been verified in specific compounds, such as glutathione metabolism, cytochrome P450 metabolism, and the p53 pathway, among others. Hepatitis symptoms, the perturbation of nine bile acids and yellow or tawny urine also had corresponding pathways, justifying our method. In conclusion, this computational systems toxicology method reveals possible toxic components and could be very helpful for understanding the mechanisms of HILI. In this way, the method might also facilitate the identification of novel hepatotoxic herbs.

Dataset Information

UPLC/MS/MS-Based Metabolomics Study of the Hepatotoxicity and Nephrotoxicity in Rats Induced by Polygonum multiflorum Thunb.

Publications

UPLC/MS/MS-Based Metabolomics Study of the Hepatotoxicity and Nephrotoxicity in Rats Induced by <i>Polygonum multiflorum</i> Thunb.

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