十八味牛黄清肝丸防治对乙酰氨基酚致小鼠急性肝损伤的量效关系及调控Keap1-Nrf2通路抗氧化应激的作用机制OA

Objective:To explore the optimal clinical dosage of Shibawei Niuhuang Qinggan Pills and its mechanism of action in the treatment of acute liver injury induced by acetaminophen(APAP).Methods:The 2.5 times clinical dose(83.33 mg·kg-1·d-1),5 times clinical dose(166.66 mg·kg-1·d-1),10 times clinical dose(333.33 mg·kg-1·d-1),20 times clinical dose(666.66 mg·kg-1·d-1)and 40 times clinical dose(1 333.32 mg·kg-1·d-1)of Shibawei Niuhuang Qinggan Pills were used for preventive administration,once a day for 7 days.The APAP acute liver injury model was replicated 12 h after the last administration,and the animals were sacrificed after 12 h.The appearance and histopathological changes of the liver were observed,and the Suzuki pathological score was per-formed.The levels of liver function in serum and oxidative stress indexes in liver tissue were tested.The expression levels of Keap1,Nrf2,HO-1,NQO1,GCLC and GCLM genes and proteins were tested by PCR and WB.Results:Shibawei Niuhuang Qinggan Pills can improve APAP-induced acute liver injury in mice,and 10 times clinical dose group has the best effect.It can improve the appear-ance of the liver and the pathological changes of liver tissue,reduce the levels of liver function indexes such as ALT,AST,TBIL and DBIL in serum,increase the levels of antioxidant indexes such as SOD and GSH in liver,and reduce the levels of MDA and GSSG in liver tissue.It can also reduce the gene and protein expression levels of Keap1 and GCLM in liver tissue,and increase the gene and protein expression levels of Nrf2,HO-1,NQO1 and GCLC oxidative stress indicators.Conclusion:Shibawei Niuhuang Qing-gan Pills can improve APAP-induced acute liver injury,and the clinical dosage(2.00 g·60 kg-1·d-1)is reasonable.Its mechanism may be related to the regulation of Keap1-Nrf2 pathway anti-oxidative stress.