四首古方解酒护肝作用对比及其机制初探

Anti-Alcohol and Liver-Protecting Effects of Four Ancient Prescriptions and the Potential Mechanisms

目的对比百杯散、石膏汤、橘皮汤、葛根散四首古方的解酒护肝作用,并探讨四首古方治疗酒精性肝病(alcoholic liver disease,ALD)的潜在机制。方法将大鼠随机分为正常组、模型组及各给药组,并以56°白酒制备大鼠醉酒模型,给予各给药组大鼠灌胃中药水煎液,正常组和模型组灌胃纯净水,记录大鼠醉酒睡眠时间,测定大鼠血乙醇浓度及血清和肝脏中乙醇脱氢酶(alcohol dehydrogenase,ADH)、乙醛脱氢酶(aldehyde dehydrogenase,ALDH)活性等。网络药理学方法分析四首方治疗ALD的有效成分、关键靶点及信号通路等。结果(1)四首古方均可显著延长醉酒模型大鼠醉酒时间,缩短醒酒时间,其中百杯散可明显改善大鼠血清ADH、ALDH活性和甘油三酯(triglyceride,TG)、谷胱甘肽(glutathione,GSH)及超氧化物歧化酶(super-oxide dismutase,SOD)含量(P<0.05);石膏汤可明显降低大鼠血清TG含量;橘皮汤能明显改善大鼠血清GSH、丙二醛(malondialdehyde,MDA)含量;葛根散可显著降低血乙醇浓度,改善大鼠血清或肝脏中ADH、ALDH、SOD活性及TG、总胆固醇(total cholesterol,TC)、谷胱甘肽转移酶(glutathione S-transferase,GST)、GSH、MDA含量(P<0.05或P<0.01);四首方均可不同程度减轻肝脏病理损伤程度,减少脂滴面积。(2)通过网络药理学方法,筛选出四首方治疗ALD共有78个靶点,其中肿瘤坏死因子(tumor necrosis factor,TNF)、蛋白激酶B1(protein kinase B1,AKT1)、雌激素受体1(estrogen receptor 1,ESR1)、表皮因子生长受体(epidermal growth factor receptor,EGFR)、细胞色素P4502C19(cytochrome P4502C19,CYP2C19)、过氧化物酶体增生激活受体α(peroxisome proliferator activated receptorα,PPARα)可能是治疗ALD的重要靶点,京都基因与基因组百科全书(Kyoto encyclopedia of genes and gnomes,KEGG)通路富集分析可能通过PPAR、腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)、TNF/PPARα-CYP2E1-ALDH信号通路发挥药效作用。结论四首古方均有一定解酒护肝作用,其中葛根散的作用更显著。四首方可能通过作用于TNF/PPARα-CYP2E1-ALDH通路调节TNF、AKT1、细胞色素P450酶2E1(cytochrome P4502E1,CYP2E1)、PPARα、ALDH等关键靶点,从而加速酒精代谢、改善脂质代谢、减轻氧化应激反应发挥治疗ALD的作用。

OBJECTIVE To compare the anti-alcohol and liver-protecting effects of four ancient prescriptions,Baibei powder,Shigao decoction,Jupi decoction and Gegen powder,and explore the potential mechanisms of the four ancient prescriptions in the treatment of alcoholic liver disease(ALD).METHODS Rats were randomly divided into normal group,model group and drug administration groups,and the rat drunken model was prepared with 56°liquor.The rats in each administration group were given Chinese medicine decoction by gavage,and the normal group and the model group were given pure water by gavage.The drunken sleep time of rats was recorded,and the blood ethanol concentration and the activities of alcohol dehydrogenase(ADH)and aldehyde dehydrogenase(ALDH)in serum and liver were measured.Network pharmacology method was used to analyze the effective components,key targets and signaling pathways of the four ancipent prescriptions in the treatment of ALD.RESULTS The four ancient prescriptions could significantly prolong the drunkenness time and shorten the sobering time of drunken model rats.Among them,Baibei powder could significantly increase the serum activities of ADH,ALDH and super-oxide dismutase(SOD)and improve triglyceride(TG)and glutathione(GSH)contents(P<0.05).Shigao decoction could significantly reduce the content of serum TG.Jupi decoction could significantly improve the serum GSH and malondialdehyde(MDA)content.Gegen powder could significantly reduce the concentration of blood ethanol,improve the activities of ADH,ALDH and SOD and the contents of TG,total cholesterol(TC),glutathione S-transferase(GST),GSH and MDA in the serum or liver(P<0.05 or P<0.01).The four prescriptions could reduce the degree of liver pathological damage and reduce the area of lipid droplets to varying degrees.Through the network pharmacology analysis,a total of 78 targets were screened out for the treatment of ALD by the four prescriptions.Among them,tumor necrosis factor(TNF),protein kinase B1(AKT1),estrogen receptor 1(ESR1),epidermal growth factor receptor(EGFR),cytochrome P4502C19(CYP2C19)and peroxisome proliferator activated receptorα(PPARα)could be used as important targets for the treatment of ALD.Kyoto encyclopedia of genes and gnomes pathway enrichment analysis showed that the ancient prescriptions may play a pharmacodynamic role through PPAR,AMP-activated protein kinase(AMPK),TNF/PPARα-CYP2E1-ALDH signaling pathway.CONCLUSION The four prescriptions all have certain anti-alcohol and liver protection effects,and the effect of Gegen powder is more significant.The four prescriptions may regulate key targets such as TNF,AKT1,cytochrome P4502E1(CYP2E1),PPARαand ALDH by acting on the TNF/PPARα-CYP2E1-ALDH pathway,thereby accelerating alcohol metabolism,improving lipid metabolism,and reducing oxidative stress.