High-intensity interval training improves hepatic redox status via Nrf2 downstream pathways and reduced CYP2E1 expression in female rats with cisplatin-induced hepatotoxicity.

Abstract

Cisplatin (CP) is an antineoplastic drug associated with various cytotoxic adverse effects, including hepatotoxicity. Exercise training may offer hepatoprotection by improving redox status. This study compared the effects of light-intensity continuous training (LICT), moderate-intensity continuous training (MICT), and high-intensity interval training (HIIT) on CP-induced hepatotoxicity in female Wistar rats. The rats were divided into five groups (n = 7): sedentary control (C + S), CP and sedentary (CP + S), CP with LICT (CP + LICT), CP with MICT (CP + MICT), and CP with HIIT (CP + HIIT). The training protocols involved eight weeks of treadmill exercise before CP administration (5 mg/kg). Seven days after CP injection, the rats were euthanized to collect blood and liver tissue samples. Our findings demonstrate that HIIT was the most effective protocol in preventing histopathological alterations and reducing oxidative and nitrosative damage markers in macromolecules, including 4-HNE (lipids), nitrotyrosine (proteins), and 8-OHdG (DNA). The reduction in these markers appears to be linked to decreased CYP2E1 levels. Moreover, HIIT activated the Nrf2 pathway and upregulated its downstream antioxidant enzymes, including SOD1, catalase, GPx, and HO-1. In conclusion, HIIT emerged as the most effective protocol for mitigating hepatic damage, likely through CYP2E1 suppression and enhancement of antioxidant defenses via Nrf2 signaling pathway activation.