Abstract
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.
Highlights
The 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 levels of alanine transaminase (ALT) were higher in the Polygonum multiflorum ethanol extract (PME) groups than in the tetrahydroxystilbene glucoside (TSG) groups, and the results indicate that the other components may induce hepatotoxicity
TSG was the main chemical component of PME and the 50% ethanol elution fraction. These results suggest that the mechanism underlying idiosyncratic PME hepatotoxicity was that TSG led to disruptions in amino acid metabolism, lipid metabolism, energy metabolism and glucose metabolism
Summary
The 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. The hepatotoxicity of PM has been summarized and recorded in the LiverTox® database, a comprehensive resource for idiosyncratic drug-induced liver injury (IDILI) produced by the National Institute of Diabetes and Digestive and Kidney Diseases and National Library of Medicine [4]. Animal models must be developed to assess drugs that cause IDILI. The inflammatory stress hypothesis has provided some of the first animal models of idiosyncratic hepatotoxicity in which nontoxic doses of IDILI-causing drugs are rendered hepatotoxic upon coexposure to a nontoxic but modestly inflammatory dose of bacterial endotoxin (lipopolysaccharide (LPS)) [8, 9]. The LPS model has been successfully used to evaluate several drugs known to cause IDILI in humans, including trovafloxacin, ranitidine, sulindac, chlorpromazine, halothane, monocrotaline, amiodarone and diclofenac [6]. The LPS model is used to evaluate the idiosyncratic hepatotoxicity of PM
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