Effect of Shuganning injection on the model of cholestasis - type chlorpromazine - induced liver injury constructed by a new tissue - engineered liver

Long HUANG; Yu CHEN; Qiao WU; Zhongping DUAN

doi:10.3969/j.issn.1001-5256.2022.03.018

Volume 38 Issue 3

Mar. 2022

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Article Navigation > Journal of Clinical Hepatology > 2022 > 38(3): 587-593

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Effect of Shuganning injection on the model of cholestasis - type chlorpromazine - induced liver injury constructed by a new tissue - engineered liver

DOI: 10.3969/j.issn.1001-5256.2022.03.018

Long HUANG^{1a, 1b},
Yu CHEN^{1a, 1b},
Qiao WU^{1a, 1b, 2
,
,
,},
Zhongping DUAN^{1a, 1b
,
,
,}

1a.
Fourth Department of Liver Disease Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
1b.
Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
2.
Center of Infectious Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China

Research funding:

Big Data Precision Medicine Advanced Innovation Center (1212040205);

Beijing Natural Science Foundation (7222094);

Capital Health Development Scientific Research Special Project (2021-1G-2181)

More Information

Corresponding author: WU Qiao, wuqiao322@163.com(ORCID: 0000-0001-7667-5002); DUAN Zhongping, duan@ccmu.edu.cn(ORCID: 0000-0002-8455-0426)
Received Date: 2021-07-13
Accepted Date: 2021-08-12
Published Date: 2022-03-20

Abstract

Abstract

Objective To investigate the effect of Shuganning injection (SGN) in alleviating drug-induced cholestasis and the possible mechanisms involved. Methods The liver of Sprague-Dawley rats was decellularized to prepare collagen scaffolds, and then the scaffolds were recellularized with human HepG2 cells to obtain the tissue-engineered liver (normal control group). The tissue-engineered liver was perfused with 10 μmol/L chlorpromazine (CPZ) and bile salt mixture to establish a model of drug-induced cholestasis (CPZ group), and the model was further treated with Shuganning injection (10³-fold dilution) as the injury protection group (SGN+CPZ group). The markers for hepatocellular injury [alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP)] and the antioxidant and oxidative stress markers [glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS)] were measured for all groups, and the normal control group, the CPZ group, and the SGN+CPZ group were compared in terms of the mRNA and protein expression levels of the enzymes associated with liver bile salt metabolism and the enzymes associated with hepatic cholestasis. HE staining was performed to observe liver pathology. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Results Compared with the CPZ group, the SGN+CPZ group had significant reductions in the markers for hepatocellular injury ALT, AST, LDH, and ALP (all P < 0.000 1), significant increases in the oxidative stress markers GSH and SOD (P < 0.000 1 and P < 0.001), and significant reductions in the markers MDA and ROS (P < 0.000 1 and P < 0.001). Compared with the CPZ group, the SGN+CPZ group had significant reductions in the mRNA expression levels of cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CPY8B1) in hepatocytes (all P < 0.001) and significant increases in the mRNA expression levels of farnesoid X receptor (FXR), small heterodimeric partner (SHP), bile salt export pump (BSEP), and multidrug resistance-associated protein 2 (MRP2) (P < 0.000 1, P < 0.01, P < 0.000 1, and P < 0.000 1). HE staining showed that compared with the CPZ group, the SGN+CPZ group had a significant reduction in hepatocyte injury and a significant increase in the number of cells. Conclusion Shuganning injection can alleviate drug-induced cholestatic liver injury caused by chlorpromazine, and it exerts a protective effect by activating FXR in hepatocytes and increasing the expression of SHP to regulate bile salt balance. It also inhibits CYP7A1 and CYP8B1 to reduce the synthesis of hydrophobic bile acids and upregulates the expression of BSEP and MRP2 to promote the excretion of bile salts.
- Chemical and Drug Induced Liver Injury,
- Cholic Acids,
- Shuganning injection,
- Rats, Sprague-Dawley

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References

[1]	SHEN T, HUANG X, WANG YY, et al. Current status of epidemiological studies on drug-induced liver injury in China[J]. J Clin Hepatol, 2018, 34(6): 1152-1155. DOI: 10.3969/j.issn. 1001-5256.2018.06.002. 沈弢, 黄昕, 王誉雅, 等. 我国药物性肝损伤流行病学研究现状[J]. 临床肝胆病杂志, 2018, 34(6): 1152-1155. DOI: 10.3969/j.issn.1001-5256.2018.06.002.
[2]	Drug-induced Liver Disease Study Group, Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the management of drug-induced liver injury[J]. J Clin Hepatol, 2015, 31(11): 1752-1769. DOI: 10.3969/j.issn.1001-5256.2015.11.002. 中华医学会肝病学分会药物性肝病学组. 药物性肝损伤诊治指南[J]. 临床肝胆病杂志, 2015, 31(11): 1752-1769. DOI: 10.3969/j.issn.1001-5256.2015.11.002.
[3]	ZENG LR, HUANG XM, YANG CY, et al. Safety, rationality and drug use of Shuganning injection[J]. Chin J Clin Ration Drug Use, 2021, 14(15): 35-37, 41. DOI: 10.15887/j.cnki.13-1389/r.2021.15.012. 曾令荣, 黄雪梅, 杨传玉, 等. 舒肝宁注射液临床应用安全性、合理性及药物利用情况分析[J]. 临床合理用药杂志, 2021, 14(15): 35-37, 41. DOI: 10.15887/j.cnki.13-1389/r.2021.15.012.
[4]	HENDRIKS DF, FREDRIKSSON PUIGVERT L, MESSNER S, et al. Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability[J]. Sci Rep, 2016, 6: 35434. DOI: 10.1038/srep35434.
[5]	DU LN, YANG Y. Establishment and application of animal models of cholestasis[J]. J Clin Hepatol, 2019, 35(2): 444-447. DOI: 10.3969/j.issn.1001-5256.2019.02.046. 杜丽娜, 杨燕. 胆汁淤积动物模型的构建及应用前景[J]. 临床肝胆病杂志, 2019, 35(2): 444-447. DOI: 10.3969/j.issn.1001-5256.2019.02.046.
[6]	ANTHÉRIEU S, BACHOUR-EL AZZI P, DUMONT J, et al. Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human HepaRG cells[J]. Hepatology, 2013, 57(4): 1518-1529. DOI: 10.1002/hep.26160.
[7]	COPPLE BL, JAESCHKE H, KLAASSEN CD. Oxidative stress and the pathogenesis of cholestasis[J]. Semin Liver Dis, 2010, 30(2): 195-204. DOI: 10.1055/s-0030-1253228.
[8]	CHATTERJEE S, ANNAERT P. Drug-induced cholestasis: Mechanisms, models, and markers[J]. Curr Drug Metab, 2018, 19(10): 808-818. DOI: 10.2174/1389200219666180427165035.
[9]	AI G, YAN YD, HUANG ZM. Research progress on Chinese materia medica in treatment of intrahepatic cholestasis based on FXR-mediated regulation[J]. Chin Tradit Herb Drug, 2017, 48(19): 4077-4088. DOI: 10.7501/j.issn.0253-2670.2017.19.028. 艾国, 颜耀东, 黄正明. 基于调控法尼醇X受体的中药治疗肝内胆汁瘀积的研究进展[J]. 中草药, 2017, 48(19): 4077-4088. DOI: 10.7501/j.issn.0253-2670.2017.19.028.
[10]	LIU YQ, CAI X, QIN RW, et al. Regulation effect of leech on farnesol X receptor pathway in rat model of intrahepatic cholestasis[J]. China Med Herald, 2021, 18(5): 4-9. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202105003.htm 刘玉青, 蔡昕, 覃仁武, 等. 水蛭对肝内胆汁淤积大鼠模型法尼醇X受体通路的调节作用[J]. 中国医药导报, 2021, 18(5): 4-9. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202105003.htm
[11]	LI YX, LI XP, GU J, et al. Study on protective mechanism of Tibetan medicine Ershiwuwei Songshi Pills on cholestatic liver injury in rats based on FXR signaling pathway[J]. China J Chin Mater Med, 2020, 45(21): 5273-5279. DOI: 10.19540/j.cnki.cjcmm.20200727.401. 李彦希, 李晓朋, 顾健, 等. 基于FXR信号通路研究藏族药二十五味松石丸对胆汁淤积型肝损伤大鼠的保护作用机制[J]. 中国中药杂志, 2020, 45(21): 5273-5279. DOI: 10.19540/j.cnki.cjcmm.20200727.401.
[12]	LU TT, REPA JJ, MANGELSDORF DJ. Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism[J]. J Biol Chem, 2001, 276(41): 37735-37738. DOI: 10.1074/jbc.R100035200.
[13]	GOODWIN B, JONES SA, PRICE RR, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis[J]. Mol Cell, 2000, 6(3): 517-526. DOI: 10.1016/s1097-2765(00)00051-4.
[14]	ZOLLNER G, MARSCHALL HU, WAGNER M, et al. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: Pathogenetic and therapeutic considerations[J]. Mol Pharm, 2006, 3(3): 231-251. DOI: 10.1021/mp060010s.
[15]	GIJBELS E, VINKEN M. Mechanisms of drug-induced cholestasis[J]. Methods Mol Biol, 2019, 1981: 1-14. DOI: 10.1007/978-1-4939-9420-5_1.
[16]	LEFEBVRE P, CARIOU B, LIEN F, et al. Role of bile acids and bile acid receptors in metabolic regulation[J]. Physiol Rev, 2009, 89(1): 147-191. DOI: 10.1152/physrev.00010.2008.
[17]	XU LJ, JIANG SD, JI H, et al. Role of bile acid nuclear receptor FXR in cholestasis and related pharmacotherapy[J]. J Pharm Res, 2018, 37(3): 169-173. DOI: 10.13506/j.cnki.jpr.2018.03.011. 徐俐洁, 蒋思达, 季晖, 等. 胆汁酸核受体FXR在胆汁淤积及其药物治疗中的研究进展[J]. 药学研究, 2018, 37(3): 169-173. DOI: 10.13506/j.cnki.jpr.2018.03.011.
[18]	MARIN JJ, MACIAS RI, BRIZ O, et al. Bile acids in physiology, pathology and pharmacology[J]. Curr Drug Metab, 2015, 17(1): 4-29. DOI: 10.2174/1389200216666151103115454.

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Effect of Shuganning injection on the model of cholestasis - type chlorpromazine - induced liver injury constructed by a new tissue - engineered liver

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Effect of Shuganning injection on the model of cholestasis - type chlorpromazine - induced liver injury constructed by a new tissue - engineered liver

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