{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:02:12Z","timestamp":1759449732293,"version":"build-2065373602"},"reference-count":49,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Amiodarone (AMD) is one of the most effective antiarrhythmic agents; however, its clinical use is limited by potential adverse effects, particularly hepatotoxicity, which occurs in 14%\u201382% of treated patients. Moreover, severe liver injury develops in approximately 1%\u20133% of cases. This study aimed to elucidate the mechanism underlying AMD\u2010induced hepatotoxicity using a HepG2 cell culture model, with a specific focus on the aryl hydrocarbon receptor (AhR), a key intracellular sensor of xenobiotics. AMD exhibited notable cytotoxicity only at concentrations between 20 and 50\u2009\u03bcM. However, at 10\u2010\u03bcM AMD significantly increased CYP1A1 and CYP1A2 enzymatic activity, as assessed by EROD and MROD assays, respectively. Additionally, low\u2010dose AMD enhanced cellular metabolism, likely as a downstream effect of CYP enzyme activation. Cotreatment with the AhR antagonist CAY10464 effectively inhibited AMD\u2010induced CYP1A1 and CYP1A2 activity but failed to mitigate cytotoxic effects. Notably, CAY10464 cotreatment further elevated catalase (CAT) activity and glutathione (GSH) levels, suggesting that AhR inhibition may exacerbate oxidative stress responses. Taken together, these findings indicate that although AhR is activated by AMD and contributes to the metabolic response, it does not mediate the primary cytotoxic effects. The hepatotoxicity observed is likely governed by alternative signaling mechanisms and\/or receptor cross\u2010talk. Thus, the role of AhR in AMD\u2010induced liver injury appears to be secondary and may reflect downstream or compensatory processes rather than direct involvement in initiating toxicity.<\/jats:p>","DOI":"10.1002\/jat.4844","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T19:35:53Z","timestamp":1751484953000},"page":"2305-2320","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aryl Hydrocarbon Receptor (AhR)\u2013Independent Amiodarone (AMD) Toxicity in HepG2 Cell Line"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2207-1160","authenticated-orcid":false,"given":"Konrad\u00a0A.","family":"Szychowski","sequence":"first","affiliation":[{"name":"Department of Biotechnology and Cell Biology, Medical College University of Information Technology and Management in Rzeszow  Rzeszow 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