Hepato-Cardiac Axis in Epirubicin Toxicity: Role of Kynurenine Pathway and N-Acetylcysteine Antioxidant Intervention.

Epirubicin (EPI) is a widely used chemotherapeutic agent; however, its clinical utility is limited by severe side effects, particularly the production of reactive oxygen species (ROS). Among these, cardiotoxicity is one of the most critical issues, and it is worsened by impaired hepatic clearance resulting from liver dysfunction. This study aimed to investigate molecular changes induced by EPI in the liver within the kynurenine pathway (KP), their possible contribution to cardiotoxicity, and the protective effects of N-acetylcysteine (NAC). Rats received intraperitoneal injections of 50 or 300 mg/kg NAC, followed 1 h later by 9.6 mg/kg EPI. Tryptophan (Trp), kynurenine (Kyn), kynurenic acid (KYNA), quinolinic acid (QA), kynureninase, and kynurenine 3-monooxygenase (KMO) levels in the liver and cleaved caspase-3 levels in the liver and heart tissue were measured using ELISA. Hepatic and cardiac total antioxidant status (TAS) and total oxidant status (TOS) were determined using a colorimetric method. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), creatine kinase-MB isoenzyme (CK-MB), high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (T-chol), and triglyceride (TG) were analyzed with a clinical biochemistry analyzer. Cardiac morphology was examined using hematoxylin-eosin staining. EPI administration was associated with increases in plasma CK-MB, the AST/ALT ratio, LDL, T-chol, and TG, with these increases partially attenuated by NAC treatment. Hepatic levels of Trp, QA, and KMO were positively correlated with plasma CK-MB and the AST/ALT ratio. Additionally, EPI appeared to increase oxidative stress in heart tissue and induce morphological changes. At the same time, NAC treatment was associated with partial improvement in these parameters, suggesting that alterations in the hepatic KP may be linked to possible cardiac involvement. Our findings suggest that EPI-induced alterations in hepatic KP may impair hepatic clearance, and NAC administration may provide partial protection, warranting further investigation of a possible hepato-cardiac interaction.