胺碘酮通过诱发免疫紊乱加剧小鼠肝毒性
Amiodarone Aggravates Liver Toxicity in Mice by Inducing Immune Dysregulation
-
摘要: 胺碘酮(amiodarone)是临床上广泛使用的第三类抗心律失常药物，临床研究已经发现长期服用胺碘酮会对人体造成副作用，包括肝毒性。鉴于人体与共生微生物形成了一个复杂的共生生态系统，口服胺碘酮对机体的影响，从药物吸收到直接或间接的药物作用，反映了药物与机体以及共生生态系统相互作用的结果。然而，胺碘酮对肝功能的影响及其潜在机制仍然知之甚少。本研究为探讨胺碘酮对肝脏的影响，建立了胺碘酮诱导小鼠模型，采用Lieber-Decarli液体饲料，分别设置200 mg·kg-1的低剂量组和600 mg·kg-1的高剂量组。研究发现胺碘酮处理28 d后，诱发小鼠肝脏转录谱发生改变，与对照组相比，胺碘酮处理组有1 634个差异基因表达显著变化，差异基因富集的KEGG信号通路包括PPAR信号通路、脂肪酸代谢信号通路、胆汁酸分泌、代谢外源物质的细胞色素P450信号通路等。此外，胺碘酮处理组肝脏结构和功能受到损伤，组织病理学分析显示肝脏出现微泡型脂肪肝，脂质新生相关的基因Acaca、Fasn和Srebf1表达上调。血清生化检测结果表明丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)水平升高，并有浓度依赖性。进一步研究发现胺碘酮引起小鼠肝脏免疫紊乱，促发Th17细胞和Th1细胞比例上调，相应的炎症因子TNF-α、TGF-β1、IL-17等也显著增加。胺碘酮也诱发脾脏Treg细胞比例下调，CD8阳性细胞比例上调。由此可知，胺碘酮可以诱导小鼠肝脏转录组发生改变，同时造成肝毒性，诱发小鼠自身免疫紊乱，进一步引发炎症反应。Abstract: Amiodarone, a commonly used Class Ⅲ antiarrhythmic drug in clinical practice, has been associated with various side effects on the human health, including liver toxicity. Given that the human body and commensal microbes form a complex symbiotic ecosystem, the impact of oral amiodarone on the body, from drug absorption to direct or indirect drug effects, reflects the outcome of interactions between the drug and organism as well as symbiotic ecosystems. However, the effects of amiodarone and its underlying mechanism on liver functions remain poorly understood. In this study, our objective was to investigate the influence of amiodarone on liver function using an amiodarone-induced mouse model. Two groups of mice were administered with Lieber-Decarli liquid diets containing 200 mg·kg-1 (low-dose group) or 600 mg·kg-1 (high-dose group) amiodarone. We found that after 28 d of amiodarone treatment, there were significant changes in the mice's liver transcriptome compared to the control group. A total of 1 634 different genes exhibited altered expression in response to amiodarone treatment, involving with enriched KEGG signaling pathways including PPAR signaling, fatty acid metabolism, bile acid secretion, and the cytochrome P450 signaling pathway in exogenous substance metabolism. Additionally, histopathological analysis revealed microvesicular steatosis and upregulation of genes related to lipid biosynthesis such as Acaca, Fasn, and Srebf1, indicating compromised liver structure and function in the amiodarone-treated group. Serum biochemical tests indicated elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which demonstrated concentration-dependent changes. Further investigation revealed that amiodarone induced immune dysregulation in the liver tissue, leading to an upregulation of Th17 and Th1 cells proportions, accompanied by a significant elevation of inflammatory factors such as TNF-α, TGF-β1, and IL-17. Furthermore, amiodarone also caused a reduction in Treg cells proportion in the spleen and an increase in CD8+ cells. Collectively, these findings provide compelling evidence for the potency of amiodarone to induce alterations in the mouse liver transcriptome, causing hepatotoxicity and triggering autoimmune disturbances followed by an inflammatory response.
-
Key words:
- amiodarone /
- mouse liver /
- liver injury /
- immune disturbance /
- inflammation /
- genes
-
-
Vassallo P, Trohman R G. Prescribing amiodarone: An evidence-based review of clinical indications[J]. JAMA, 2007, 298(11): 1312-1322 World Health Organization (WHO). WHO model list of essential medicines[R]. Geneva: WHO, 2015 Zuo K, Li J, Li K B, et al. Disordered gut microbiota and alterations in metabolic patterns are associated with atrial fibrillation[J]. GigaScience, 2019, 8(6): giz058 Eskes S A, Wiersinga W M. Amiodarone and thyroid[J]. Best Practice & Research Clinical Endocrinology & Metabolism, 2009, 23(6): 735-751 Colunga Biancatelli R M, Congedo V, Calvosa L, et al. Adverse reactions of amiodarone[J]. Journal of Geriatric Cardiology, 2019, 16(7): 552-566 Oliveira M, Melo N, Mota P C, et al. Pleuroparenchymal fibroelastosis as another potential lung toxicity pattern induced by amiodarone[J]. Archivos De Bronconeumologia, 2020, 56(1): 55-56 Matuskova Z, Anzenbacherova E, Vecera R, et al. Administration of a probiotic can change drug pharmacokinetics: Effect of E. coli Nissle 1917 on amidarone absorption in rats[J]. PLoS One, 2014, 9(2): e87150 Ingram D V, Jaggarao N S, Chamberlain D A. Ocular changes resulting from therapy with amiodarone[J]. The British Journal of Ophthalmology, 1982, 66(10): 676-679 Raja K, Thung S N, Fiel M I, et al. Drug-induced steatohepatitis leading to cirrhosis: Long-term toxicity of amiodarone use[J]. Seminars in Liver Disease, 2009, 29(4): 423-428 Farrell G C. Drugs and steatohepatitis[J]. Seminars in Liver Disease, 2002, 22(2): 185-194 Lewis J H, Ranard R C, Caruso A, et al. Amiodarone hepatotoxicity: Prevalence and clinicopathologic correlations among 104 patients[J]. Hepatology, 1989, 9(5): 679-685 Neshat S Y, Quiroz V M, Wang Y J, et al. Liver disease: Induction, progression, immunological mechanisms, and therapeutic interventions[J]. International Journal of Molecular Sciences, 2021, 22(13): 6777 Hann A, Oo Y H, Perera M T P R. Regulatory T-cell therapy in liver transplantation and chronic liver disease[J]. Frontiers in Immunology, 2021, 12: 719954 Duryee M J, Klassen L W, Thiele G M. Immunological response in alcoholic liver disease[J]. World Journal of Gastroenterology, 2007, 13(37): 4938-4946 Berson A, De Beco V, Lettéron P, et al. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes[J]. Gastroenterology, 1998, 114(4): 764-774 Farrell G C. Drugs and steatohepatitis[J]. Seminars in Liver Disease, 2002, 22(2): 185-194 Essrani R, Mehershahi S, Essrani R K, et al. Amiodarone-induced acute liver injury[J]. Case Reports in Gastroenterology, 2020, 14(1): 87-90 Young T A, Cunningham C C, Bailey S M. Reactive oxygen species production by the mitochondrial respiratory chain in isolated rat hepatocytes and liver mitochondria: Studies using myxothiazol[J]. Archives of Biochemistry and Biophysics, 2002, 405(1): 65-72 Serviddio G, Bellanti F, Giudetti A M, et al. Mitochondrial oxidative stress and respiratory chain dysfunction account for liver toxicity during amiodarone but not dronedarone administration[J]. Free Radical Biology and Medicine, 2011, 51(12): 2234-2242 赵圣刚, 陈善浆, 张冉, 等. 决奈达隆和胺碘酮对大鼠肝脏功能及组织的影响[J]. 中国心脏起搏与心电生理杂志, 2013, 27(5): 441-444 Zhao S G, Chen S J, Zhang R, et al. The effect of dronedarone and amiodarone on hepatic function and morphology in rats[J]. Chinese Journal of Cardiac Pacing and Electrophysiology, 2013, 27(5): 441-444(in Chinese)
Ernst M C, Sinal C J, Pollak P T. Influence of peroxisome proliferator-activated receptor-alpha (PPARα) activity on adverse effects associated with amiodarone exposure in mice[J]. Pharmacological Research, 2010, 62(5): 408-415 Wu Q, Zhang X N, Zhao Y, et al. High l-carnitine ingestion impairs liver function by disordering gut bacteria composition in mice[J]. Journal of Agricultural and Food Chemistry, 2020, 68(20): 5707-5714 Zhang P, Zheng L Y, Duan Y T, et al. Gut microbiota exaggerates triclosan-induced liver injury via gut-liver axis[J]. Journal of Hazardous Materials, 2022, 421: 126707 Halder R C, Seki S, Weerasinghe A, et al. Characterization of NK cells and extrathymic T cells generated in the liver of irradiated mice with a liver shield[J]. Clinical and Experimental Immunology, 1998, 114(3): 434-447 Blasco-Algora S, Masegosa-Ataz J, Gutiérrez-García M L, et al. Acute-on-chronic liver failure: Pathogenesis, prognostic factors and management[J]. World Journal of Gastroenterology, 2015, 21(42): 12125-12140 Hensley M K, Deng J C. Acute on chronic liver failure and immune dysfunction: A mimic of sepsis[J]. Seminars in Respiratory and Critical Care Medicine, 2018, 39(5): 588-597 Triantafyllou E, Woollard K J, McPhail M J W, et al. The role of monocytes and macrophages in acute and acute-on-chronic liver failure[J]. Frontiers in Immunology, 2018, 9: 2948 Casulleras M, Zhang I W, López-Vicario C, et al. Leukocytes, systemic inflammation and immunopathology in acute-on-chronic liver failure[J]. Cells, 2020, 9(12): 2632 Wandrer F, Frangež Ž, Liebig S, et al. Autophagy alleviates amiodarone-induced hepatotoxicity[J]. Archives of Toxicology, 2020, 94(10): 3527-3539 Rhodes A, Eastwood J B, Smith S A. Early acute hepatitis with parenteral amiodarone: A toxic effect of the vehicle?[J]. Gut, 1993, 34(4): 565-566 Lu J T, Jones A D, Harkema J R, et al. Amiodarone exposure during modest inflammation induces idiosyncrasy-like liver injury in rats: Role of tumor necrosis factor-alpha[J]. Toxicological Sciences: An Official Journal of the Society of Toxicology, 2012, 125(1): 126-133 Meng X, Mojaverian P, Doedée M, et al. Bioavailability of amiodarone tablets administered with and without food in healthy subjects[J]. The American Journal of Cardiology, 2001, 87(4): 432-435 Erez N, Hubel E, Avraham R, et al. Hepatic amiodarone lipotoxicity is ameliorated by genetic and pharmacological inhibition of endoplasmatic reticulum stress[J]. Toxicological Sciences: An Official Journal of the Society of Toxicology, 2017, 159(2): 402-412 Rabinowich L, Shibolet O. Drug induced steatohepatitis: An uncommon culprit of a common disease[J]. BioMed Research International, 2015, 2015: 168905 Vitins A P, Kienhuis A S, Speksnijder E N, et al. Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models[J]. Archives of Toxicology, 2014, 88(8): 1573-1588 Fromenty B, Fisch C, Labbe G, et al. Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice[J]. The Journal of Pharmacology and Experimental Therapeutics, 1990, 255(3): 1371-1376 Soyama A, Hanioka N, Saito Y, et al. Amiodarone N-deethylation by CYP2C8 and its variants, CYP2C8*3 and CYP2C8 P404A[J]. Pharmacology & Toxicology, 2002, 91(4): 174-178 Takai S, Oda S, Tsuneyama K, et al. Establishment of a mouse model for amiodarone-induced liver injury and analyses of its hepatotoxic mechanism[J]. Journal of Applied Toxicology, 2016, 36(1): 35-47 Lee G R. The balance of Th17 versus Treg cells in autoimmunity[J]. International Journal of Molecular Sciences, 2018, 19(3): 730 Guillot A, Tacke F. Liver macrophages: Old dogmas and new insights[J]. Hepatology Communications, 2019, 3(6): 730-743 Elsegood C L, Chan C W, Degli-Esposti M A, et al. Kupffer cell-monocyte communication is essential for initiating murine liver progenitor cell-mediated liver regeneration[J]. Hepatology, 2015, 62(4): 1272-1284 Castro G, Liu X J, Ngo K, et al. RORγt and RORα signature genes in human Th17 cells[J]. PLoS One, 2017, 12(8): e0181868 Ciofani M, Madar A, Galan C, et al. A validated regulatory network for Th17 cell specification[J]. Cell, 2012, 151(2): 289-303 Kocak M Z. Oral amiodarone-induced liver injury, especially gamma glutamyl transferase elevation: A case report[J]. Eurasian Journal of Medicine and Oncology, 2017, 2: 2 Guigui B, Perrot S, Berry J P, et al. Amiodarone-induced hepatic phospholipidosis: A morphological alteration independent of pseudoalcoholic liver disease[J]. Hepatology, 1988, 8(5): 1063-1068 Nguyen C L, Markey K A, Miltiadous O, et al. High-resolution analyses of associations between medications, microbiome, and mortality in cancer patients[J]. Cell, 2023, 186(12): 2705-2718.e17 -
点击查看大图
计量
- 文章访问数: 1102
- HTML全文浏览数: 1102
- PDF下载数: 168
- 施引文献: 0
下载:
