药学学报, 2021, 56(4): 1147-1154
引用本文:
徐乐千#, 周艳莹#, 姜伊鸣, 邢云惠, 黄民, 毕惠嫦*. 五酯片不同给药间隔抵抗扑热息痛所致肝损伤的作用及机制研究[J]. 药学学报, 2021, 56(4): 1147-1154.
XU Le-qian#, ZHOU Yan-ying#, JIANG Yi-ming, XING Yun-hui, HUANG Min, BI Hui-chang*. Wuzhi Tablet protects against APAP-induced liver injury at different pretreated intervals in mice[J]. Acta Pharmaceutica Sinica, 2021, 56(4): 1147-1154.

五酯片不同给药间隔抵抗扑热息痛所致肝损伤的作用及机制研究
徐乐千#, 周艳莹#, 姜伊鸣, 邢云惠, 黄民, 毕惠嫦*
中山大学药学院, 药物代谢与药动学实验室, 广东 广州 510006
摘要:
扑热息痛(paracetamol)又称对乙酰氨基酚(acetaminophen,APAP),其导致的药源性肝损伤在世界范围内普遍存在。五酯片(南五味子醇浸膏,Wuzhi Tablet,WZ)是临床上常用的护肝药。作者前期研究表明,WZ预处理三天后与APAP同时给药可抵抗APAP所致肝损伤,但单次给予WZ与APAP不同给药间隔对肝损伤的作用及机制尚不清楚。本文研究了单次给予WZ与APAP不同间隔给药后的肝损伤指标变化、APAP代谢物生成情况和细胞色素P450(cytochrome P450,CYP450)代谢酶活性,考察了WZ单次不同给药间隔抵抗APAP所致肝损伤的作用及机制。动物实验经中山大学动物伦理委员会审核通过。结果表明,单次给予WZ 0、0.5及2 h后再给予APAP,均可显著减轻APAP所致肝损伤,其机制为抑制CYP450酶介导的APAP代谢激活,减少APAP毒性代谢物的生成。本研究进一步确证了WZ与APAP间隔0、0.5及2 h给药具有显著抵抗APAP所致肝损伤的作用,WZ通过抑制APAP代谢激活相关的CYP450酶活性,从而抵抗APAP所致肝损伤,为五酯片防治APAP所致肝损伤提供新数据。
关键词:    五酯片      对乙酰氨基酚      药源性肝损伤      给药间隔      CYP450代谢酶     
Wuzhi Tablet protects against APAP-induced liver injury at different pretreated intervals in mice
XU Le-qian#, ZHOU Yan-ying#, JIANG Yi-ming, XING Yun-hui, HUANG Min, BI Hui-chang*
Lab of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
Abstract:
Acetaminophen (APAP, also known as paracetamol)-induced liver injury is the leading cause of drug-induced liver injury in the world. Wuzhi Tablet (WZ, an ethanol extract of Schisandra sphenanthera) is widely used in clinical practice to protect liver function. Our previous studies have shown that pretreatment with WZ for 3 days can significantly protect against APAP-induced liver injury; however, the effect of different intervals between APAP and WZ treatment on APAP-induced liver injury remains unclear. In this study, the change in liver injury indexes, APAP metabolites, and the activity of cytochrome P450 (CYP450) enzymes after treatment with WZ and APAP at different intervals were determined. The animal experiment was reviewed and approved by the Animal Ethics Committee of Sun Yat-sen University. The results show that 0 h, 0.5 h, and 2 h pretreatment with WZ significantly protected against APAP-induced liver injury in mice, as evidenced by a significant decrease in biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malonaldehyde (MDA). WZ inhibited the metabolic activation of APAP mediated by CYP450 enzymes and reduced the formation of APAP metabolites. This study further demonstrates that pretreatment with WZ at different intervals (0 h, 0.5 h, and 2 h before APAP dosing) exerts a significant hepatoprotective effect against APAP-induced liver injury, and a single-dose of WZ inhibits the activity of CYP450 enzymes related to APAP metabolic activation, thereby protecting against APAP-induced hepatotoxicity.
Key words:    Wuzhi Tablet    acetaminophen    drug-induced liver injury    dosing interval    CYP450 enzyme   
收稿日期: 2021-03-11
DOI: 10.16438/j.0513-4870.2021-0361
基金项目: 国家自然科学基金资助项目(81973392,82025034).
通讯作者: 毕惠嫦,Tel:86-20-39943470,Fax:86-20-39943000,E-mail:bihchang@mail.sysu.edu.cn
Email: bihchang@mail.sysu.edu.cn
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参考文献:
[1] Schilling A, Corey R, Leonard M, et al. Acetaminophen:old drug, new warnings[J]. Cleve Clin J Med, 2010, 77:19-27.
[2] Katarey D, Verma S. Drug-induced liver injury[J]. Clin Med (Lond), 2016, 16:104-109.
[3] Bernal W, Lee WM, Wendon J, et al. Acute liver failure:a curable disease by 2024?[J]. J Hepatol, 2015, 62:112-120.
[4] McGill MR, Jaeschke H. Metabolism and disposition of acetaminophen:recent advances in relation to hepatotoxicity and diagnosis[J]. Pharm Res, 2013, 30:2174-2187.
[5] Athersuch TJ, Antoine DJ, Boobis AR, et al. Paracetamol metabolism, hepatotoxicity, biomarkers and therapeutic interventions:a perspective[J]. Toxicol Res (Camb), 2018, 7:347-357.
[6] Gonzalez FJ. The use of gene knockout mice to unravel the mechanisms of toxicity and chemical carcinogenesis[J]. Toxicol Lett, 2001, 120:199-208.
[7] Luo DD, Chen JF, Liu JJ, et al. Tetrahydrocurcumin and octahydrocurcumin, the primary and final hydrogenated metabolites of curcumin, possess superior hepatic-protective effect against acetaminophen-induced liver injury:role of CYP2E1 and Keap1-Nrf2 pathway[J]. Food Chem Toxicol, 2019, 123:349-362.
[8] Wang YX, Du Y, Liu XF, et al. A hepatoprotection study of Radix Bupleuri on acetaminophen-induced liver injury based on CYP450 inhibition[J]. Chin J Nat Med, 2019, 17:517-524.
[9] Szopa A, Ekiert R, Ekiert H. Current knowledge of Schisandra chinensis (Turcz.) Baill. (Chinese magnolia vine) as a medicinal plant species:a review on the bioactive components, pharmacological properties, analytical and biotechnological studies[J]. Phytochem Rev, 2017, 16:195-218.
[10] Jiang Y, Fan X, Wang Y, et al. Hepato-protective effects of six schisandra lignans on acetaminophen-induced liver injury are partially associated with the inhibition of CYP-mediated bioactivation[J]. Chem Biol Interact, 2015, 231:83-89.
[11] Jiang Y, Fan X, Wang Y, et al. Schisandrol B protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of liver regeneration[J]. Toxicol Sci, 2015, 143:107-115.
[12] Fan X, Chen P, Jiang Y, et al. Therapeutic efficacy of Wuzhi tablet (Schisandra sphenanthera extract) on acetaminophen-induced hepatotoxicity through a mechanism distinct from N-acetylcysteine[J]. Drug Metab Dispos, 2015, 43:317-324.
[13] Fan X, Jiang Y, Wang Y, et al. Wuzhi tablet (Schisandra Sphenanthera extract) protects against acetaminophen-induced hepatotoxicity by inhibition of CYP-mediated bioactivation and regulation of NRF2-ARE and p53/p21 pathways[J]. Drug Metab Dispos, 2014, 42:1982-1990.
[14] Zhou Y, Fan X, Jiao T, et al. SIRT6 as a key event linking P53 and NRF2 counteracts APAP-induced hepatotoxicity through inhibiting oxidative stress and promoting hepatocyte proliferation[J]. Acta Pharm Sin B, 2021, 11:89-99.
[15] Qin XL, Li JL, Wang SH, et al. Co-administration of Wuzhi tablet (Schisandra sphenanthera extract) alters tacrolimus pharmacokinetics in a dose- and time-dependent manner in rats[J]. J Ethnopharmacol, 2020, 263:113233.
[16] Qin X, Duan W, Li L, et al. Effect of long-term treatment of Wuzhi tablet on the expression and activity of cytochrome P4503A in rats[J]. Acta Pharm Sin (药学学报), 2016, 51:1407-1411.
[17] Qin XL, Chen X, Wang Y, et al. In vivo to in vitro effects of six bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) on the CYP3A/P-glycoprotein-mediated absorption and metabolism of tacrolimus[J]. Drug Metab Dispos, 2014, 42:193-199.
[18] Qin XL, Chen X, Zhong GP, et al. Effect of Tacrolimus on the pharmacokinetics of bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) and the potential roles of CYP3A and P-gp[J]. Phytomedicine, 2014, 21:766-772.
[19] Qin XL, Bi HC, Wang CX, et al. Study of the effect of Wuzhi tablet (Schisandra sphenanthera extract) on tacrolimus tissue distribution in rat by liquid chromatography tandem mass spectrometry method[J]. Biomed Chromatogr, 2010, 24:399-405.