title: Hepatotoxic assessment of Polygoni Multiflori Radix extract and toxicokinetic study of stilbene glucoside and anthraquinones in rats.
abstract: BACKGROUND
  Polygoni Multiflori Radix (PMR) has been traditionally used as a tonic and an anti-aging remedy for centuries; however, hepatic lesions linked to PMR have been frequently reported.
  
  
  OBJECTIVE
  This work attempted to investigate the hepatotoxic potential of PMR extract and the toxicokinetics of stilbene glucoside and anthraquinones in PMR extract following repeated administration.
  
  
  METHODS
  Histopathological and biochemical tests were performed to assess the hepatotoxicity of PMR extract. A rapid and sensitive liquid chromatography-mass spectrometry (LC-MS) assay was developed for toxicokinetic analysis of the main constituents of PMR extract, including 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), emodin-8-O-β-D-glucoside and emodin.
  
  
  RESULTS
  The histopathological and biochemical tests indicated that repeated administration of high-dose PMR extract (20 g/kg) for 3 weeks could cause hepatic lesions, while the low-dose treatment (1 g/kg) was safe. Necrosis and steatosis of hepatic cells, inflammatory cell infiltration and mild fibrosis were the main toxicity symptoms caused by high-dose PMR extract in rat liver. The aspartate aminotransferase (AST) levels increased by approximately 17%, from 110.80±0.84 to 129.75±10.83 IU/L, in the high-dose group compared with the control group. The proposed LC-MS method was proven to be suitable for the simultaneous quantification of these three constituents by affording desirable linearity (r(2)>0.998) and satisfactory precision (error less than 10%). The toxicokinetic study showed that emodin could not be detected in the low-dose group, but the AUC and Cmax of emodin displayed a gradual increase with repeated treatments in the high-dose group. The toxicokinetics of TSG in the low- and high-dose groups exhibited similar trends after repeated administration.
  
  
  CONCLUSIONS
  Consideration needs to be given to the rational application of PMR in the clinic to balance its benefits and risks. The increased emodin exposure in vivo provided a putative explanation for the observed hepatic lesions induced by PMR extract, although further studies to confirm the potentially causal link between emodin exposure and hepatic lesions are still necessary.
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tong jia Lane, Nanjing 210009, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tong jia Lane, Nanjing 210009, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tong jia Lane, Nanjing 210009, China.
authors.forename: Yi-Sheng
authors.initials: YS
authors.lastname: He
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), No. 24 Tong jia Lane, Nanjing 210009, China. Electronic address: cpuli@163.com.
authors.forename: Hui-Jun
authors.initials: HJ
authors.lastname: Li
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology; D004642:Emodin / Q000031:analogs & derivatives / Q000097:blood; D005960:Glucosides / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D010936:Plant Extracts / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D018517:Plant Roots; D028502:Polygonum; D017207:Rats, Sprague-Dawley; D013267:Stilbenes / Q000097:blood; D066007:Toxicokinetics
chemical_list: C489707:2',3',4',5'-tetrahydroxystilbene-2-O-beta-D-glucoside; D005960:Glucosides; D010936:Plant Extracts; D013267:Stilbenes; C008905:physcione; D004642:Emodin
keywords: 2,3,5,4′-tetrahydroxystilbene-2-O-β-d-glucoside (PubChem CID: 5321884); Emodin (PubChem CID: 3220); Emodin exposure; Emodin-8-O-β-d-glucoside (PubChem CID: 99649); Extensive consumption; Hepatocellular damage; Physcion (PubChem CID: 10639); Physcion-8-O-β-d-glucoside (PubChem CID: 5319323); Polygoni Multiflori Radix; Resveratrol (PubChem CID: 445154); Toxicokinetics