Paracetamol hepatotoxicity against the background of chronic stress: morphology and antioxidant gene activity in rats

Introduction. The study is devoted to the investigation of the effect of chronic stress on the toxic effect of paracetamol on the liver in rats. Paracetamol, widely used as an analgesic and antipyretic, can cause hepatotoxicity associated with the formation of reactive oxygen species and the development of oxidative stress when overdosed. Antioxidant mechanisms of the body’s defense include key genes such as Hmox1, Sod1, and Nqo1, which regulate the redox balance. Chronic stress reduces glutathione levels, which increases the vulnerability of the liver to toxic effects. The purpose of the work is to assess the toxicity of paracetamol in rats under the influence of chronic stress to develop new preventive approaches.Materials and methods. The experiment involved four groups of white outbred rats (6 males and 6 females), which were administered paracetamol (1000 mg/kg) and modelled chronic stress. Results. Morphological, biochemical, and genetic analyses were performed, and the liver weight coefficient was detected. In males, the liver weight coefficient varied: the minimum value (25.02) was recorded in the Stress group, the maximum (32.27) in the control group (p=0.001). In females in the «Stress» group, it was 34.77, which is lower compared to the «Paracetamol» (39.21; p=0.017) and «Paracetamol+Stress» (39.24; p=0.026) groups. Histomorphological analysis revealed signs of necrosis and inflammation with combined exposure. Genetic analysis showed an increase in Sod1 gene expression in males in the «Stress» group (p=0.001) and the highest Nqo1 level in the group with combined exposure to factors. Biochemical changes included decreased AST and ALT levels under stress and paracetamol.Limitations. For the experiment, laboratory animals of one biological species were used, and the toxicant was used in the only one concentration.Conclusion. The obtained results highlight the need for further study of the interaction of chronic stress and toxic factors for the development of preventive measures.Compliance with ethical standards. The study protocol was approved by the local ethics committee of the Ufa Research Institute of Occupational Medicine and Human Ecology (Approval No. 01-02 from 08.02.2024). Throughout the study, the animals were kept in standard conditions with 12-hour artificial lighting during the daytime, a relatively constant level of humidity (30–70%) and an air temperature of 20–25 °C. All animal manipulations were carried out in strict compliance with the rules prescribed in the basic regulatory documents, including the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg, 1986) and the Helsinki Declaration on the Humane Treatment of Animals.Contribution: Gizatullina A.A. – study concept and design, collection and processing of material, statistical processing, writing the text; Karimov D.O. – study concept and design, statistical processing; Yakupova T.G., Ryabova Yu.V., Kudoyarov E.R., Khusnutdinova N.Yu. – collection and processing of material; Valova Ya.V. – collection and processing of material, statistical processing; Smolyankin D.A. – editing. All authors are responsible for the integrity of all parts of the manuscript and approval of the manuscript final version.Conflict of interest. The authors declare no conflict of interest.Funding. Industry research program of the Federal Service for Supervision in Protection of the Rights of Consumer and Man Wellbeing (Rospotrebnadzor) for 2021–2025 “Scientific substantiation of the national system for ensuring sanitary and epidemiological welfare, managing health risks and improving the quality of life of the population of Russia”, on the topic: 6.9.1.2 “Study of the impact of chemical production factors under conditions of chronic stress” No. NIOKTR I124021200153-3.Received: January 30, 2025 / Revised: March 5, 2025 / Accepted: March 26, 2025 / Published: June 27, 2025