Influence of drug metabolizing enzyme inhibitors on liver injury susceptibility to trans-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside / 药学学报

By using the drug metabolizing enzyme inhibitors, the effects of metabolic factors on potential liver injury induced by the main component, trans-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside(trans-SG), in Polygonum multiflorum was investigated. The main metabolic enzyme isoforms involved in trans-SG metabolism were also screened. The results showed that trans-SG at the dosage 31 mg·kg-1 did not cause liver injury; and the combination of trans-SG with the phase I metabolic enzyme inhibitor, 1-benzylimidazole (10 mg·kg-1), did not change the degree of liver injury(compared with LPS + trans-SG group, P > 0.05). However, the combination of trans-SG with phase II metabolic enzyme inhibitor, ketoconazole(35 mg·kg-1), significantly increased the degree of liver injury(compared with LPS + trans-SG group, P < 0.05). The phase I metabolites of trans-SG were not detected in human liver microsomes phase I metabolism system, while the phase II trans-SG metabolites were detected in recombinant human UGT isozymes phase II metabolism system. Six isoforms of uridine diphosphate glucuronate transferase(UGT)exhibited abilities to metabolize trans-SG and the order of metabolic ability was: UGT1A1 > UGT1A9 > UGT1A7 > UGT1A10 > UGT2B7 > UGT1A8. The results showed that trans-SG was mainly metabolized by UGT in phase II metabolism. The inhibition of drug metabolizing enzymes of phase II can increase the liver injury susceptibility of trans-SG, which provides a reference to the evaluation of susceptible factors and drug incompatibility research of Polygonum multiflorum.

Comparison of processed and crude Polygoni Multiflori Radix induced rat liver injury and screening for sensitive indicators / 中国中药杂志

To investigate the difference of liver injury in rats gavaged with crude and processed Polygoni Multiflori Radix. The 75% ethanol extract of crude and processed Polygoni Multiflori Radix (50 g · kg(-1) crude medicine weight/body weight) were continuous oral administered to rats for 6 weeks. Serum biochemical indicators were dynamically detected, the change of liver histopathology was assessed 6 weeks later. Principal component analysis (PCA) was adopted to screen sensitive indicator of the liver damage induced by polygoni multiflori radix. Biochemical tests showed that the crude Polygoni Multiflori Radix group had significant increase of serum ALT, AST, ALP, DBIL and TBIL (P < 0.01 or P < 0.05) and significant decreases of serum IBIL and TBA (P < 0.01 or P < 0.05), while the processed Polygoni Multiflori Radix group showed no obvious changes, compared to the untreated normal group. Histopathologic analysis revealed that crude Polygoni Multiflori Radix group exhibited significant inflammatory cells infiltration in portal area around the blood vessels, tissue destruction and local necrosis of liver cells. There were not obvious pathological changes in processed Polygoni Multiflori Radix group. The results demonstrated that the injury effect of processed Polygoni Multiflori Radix on liver injury of rats was significantly lower than that of unprocessed, and that processing can effectively reduce the hepatotoxicity of Polygoni Multiflori Radix. Traditional transaminase liver function indicators were not sensitive for crude Polygoni Multiflori Radix induced liver damage. The serum content of DBIL and TBIL can reflect the liver damage induced by crude Polygoni Multiflori Radix early and can be sensitive indicators for clinical monitoring the usage of it.

The toxic and protective effects of Polygonum multiflorum on normal and liver injured rats based on the symptom-based prescription theory / 药学学报

The dosage-efficacy/toxicity relationship of the 50% alcohol extracts of Polygonum multiflorum was comparatively investigated on either normal or CCl4-induced chronic liver injury rats, by determining the general condition, serum biochemical indices and liver histopathology, coupled with the factor analysis. The dosages were 10 and 20 g raw materials per kg body weight. Compared with the normal control group, the normal high dose group showed significant increases of the serum alanine transaminase (ALT), total bilirubin (TBIL), high mobility group box 1 (HMGB-1) and interleukin-1β (IL-1β) (P < 0.05 or P < 0.01), as well the frequent incidences of inflammatory cell infiltration, hepatic sinus enlargement and fiber stripes formation in histopathological sections. Compared with the model control group, the model low dose group showed significant declines of serum ALT, aspartate transaminase (AST) and total bile acid (TBA) (P < 0.05), as well the alleviation of vacuoles of hepatocytes, but no amelioration of the inflammatory cell infiltration and fibrous tissue hyperplasia; moreover, the model high dose group showed significant degeneration declines of serum HMGB-1, tumor necrosis factor-α (TNF-α) and IL-1β (P < 0.05, P < 0.01), as well the evident alleviation of vacuoles degeneration of hepatocytes, inflammatory cells infiltration and fibrosis degree. The factor analysis showed that the low dosage treatment had almost neither injuring effect on the normal rats nor protective effect on the model rats; while the high dosage treatment showed observable injuring effect on the normal rats, expressed by the significant increases of the factor-1 (HMGB-1, TNF-α and IL-1β as the main contributors) and factor-2 (TBIL, ALT and TBA as the main contributors) relative to the normal control group. The liver protective effect of the high dosage treatment could be observed with the significant reduction of the factor-1, indicating the effective alleviation of the expression of inflammatory cytokines. In conclusion, it could illustrated the phenomenon of symptom-based prescription theory of Polygonum multiflorum on rat livers: the high dosage of the herb had either an injuring effect on normal rats, or a therapeutic effect on the rats with chronic liver injury.

The idiosyncratic hepatotoxicity of Polygonum multiflorum based on endotoxin model / 药学学报

The liver injury induced by Polygonum multiflorum Thunb. (PM) was investigated based on idiosyncratic hepatotoxicity model co-treated with lipopolysaccharide (LPS) at a non-hepatotoxic dose. Sprague-Dawley (SD) rats were intragastrically administered with three doses (18.9, 37.8, 75.6 g crude drug per kg body weight) of 50% alcohol extracts of PM alone or co-treated with non-toxic dose of LPS (2.8 mg·kg(-1)) via tail vein injection. The plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were assayed and the isolated livers were evaluated for histopathological changes. The dose-toxicity relationships of single treatment of PM or co-treatment of LPS were investigated comparatively to elucidate the idiosyncratic hepatotoxicity of PM. The results showed that no significant alterations of plasma ALT and AST activities were observed in the groups of solo-administration of LPS (2.8 mg·kg(-1), i.v.) or different dosage (18.9, 37.8 and 75.6 g·kg(-1), i.g.) of PM, compared to normal control group (P > 0.05); while significant elevations were observed in the co-administration groups of PM and LPS. Treatment with LPS alone caused slight infiltration of inflammatory cells in portal area but no evident hepatocytes injury. Co-treatment with LPS and PM (75.6 g·kg(-1), i.g.) caused hepatocyte focal necrosis, loss of central vein intima and a large number of inflammatory cell infiltration in portal areas. When further reduce the dosage of PM, significant increases of plasma ALT and AST activities (P < 0.05) were still observed in co-administration groups of LPS and PM (1.08 or 2.16 g·kg(-1)), but not in LPS or PM solo-administration groups. Nevertheless, the co-treatment of low dosage of PM (0.54 g·kg(-1)) with LPS did not induce any alteration of plasma ALT and AST. In conclusion, intragastric administration with 75.6 g·kg(-1) of PM did not induce liver injury in normal rats model; while the 2 folds of clinical equivalent dose of PM (1.08 g·kg(-1)) could result in liver injury in the LPS-based idiosyncratic hepatotoxicity model, which could be used to evaluate the idiosyncratic hepatotoxicity of PM.

Quality evaluation and control of Polygoni Multiflori Radix based on chemical fingerprint and toxicity monitoring / 中草药

Objective: Recently hepatotoxicity induced by Polygoni Multiflori Radix Praeparata (PMRP) frequently happened. To aim at dealing with the problems of latest increase of online shopping PMRP and lack of quality monitoring mechanism, the quality and hepatotoxicity of various batches of online shopping PMRP were analyzed, the toxicity-attenuation effects of various processing technologies of Polygoni Multiflori Radix (PMR) were compared, and the reference for clinical safe medication of PMR was provided. Methods: The quality variance of these PMRP was evaluated and the hepatotoxicity-attenuation effects of various processing technologies were compared by adopting index component content determination, chemical fingerprint, and liver cell toxicity evaluation. Results: The content of diphenylethylene glycosides in 26 batches of online shopping PMRP was 0.004%-3.442%, therein eight batches could not conform to Chinese Pharmacopoeia 2010; The chemical fingerprint similarity was between 0.052 and 0.998, therein great differences among six batches existed; The hepatotoxicity difference was significant as 9.7 times, therein the toxicity of four groups of online shopping PMRP samples was higher than that of PMR medicinal material. The toxicity of PMRP attenuated slowly using atmospheric pressure steaming method, and the toxicity by steaming 12 h declined only 13.6%; The toxicity of PMRP attenuated relatively fast by high-pressure steaming and high-pressure black soya bean steaming methods, and the toxicity by steaming 5-6 h declined by 22.1% and tended towards stability. Conclusion: The quality of online shopping PMRP varies greatly and inadequate processing method increases the liver poisoning risk of PMRP to some extent, which indicates that the researches on technology standardization of PMRP should be strengthened. As well, the high-pressure steaming method can ensure the safety of PMRP and shorten the processing time greatly, which should be expected as a promising processing method.