Amiodarone Aggravates Liver Toxicity in Mice by Inducing Immune Dysregulation
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 u-sing 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 bio-chemical 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.
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