Influence of Doxorubicin on the Development of Oxidative-Nitrosative Stress in the Liver of Rats Under Conditions of Chronic Alcoholic Hepatitis

Abstract

Introduction. Chronic alcohol consumption leads to oxidative-nitrosative liver injury, which induces the release of cytokines and growth factors, leading to activation of hepatic stellate cells and fibrosis. Modern studies have revealed a close connection between AMP-activated protein kinase and fibrogenesis. The aim of the study – to determine the effect of inhibition of AMP-activated protein kinase by the administration of doxorubicin on the development of oxidative-nitrosative stress in the liver of rats under conditions of long-term administration of ethanol. Research Methods. Experiments were performed on 24 white, sexually mature male Wistar rats, weighing 180-220 g. Chronic alcoholic hepatitis was modeled by the method of forced intermittent alcoholization according to Yu.M. Stepanov (2017). Doxorubicin was administered at a dose of 1.25 mg/kg IV 4 times a week throughout the experiment, which lasted 63 days. The activity of NO-synthase isoforms, the concentration of nitrite and peroxynitrite, the activity of arginase, superoxide dismutase and catalase, the concentration of malondialdehyde, oxidation-modified proteins, nitrosothiols and sulfide anion, and the production of superoxide anion were determined in the homogenate of the liver of rats. The significance of the differences was assessed by the Mann-Whitney U-test at p<0.05. Results and Discussion. Administration of doxorubicin under the conditions of chronic alcoholic hepatitis modeling reduced the activity of the inducible isoform of NO-synthase by 4 times, the activity of superoxide dismutase by 1.95 times and increased the activity of catalase by 1.77 times in the liver of rats compared to chronic alcoholic hepatitis. Under these conditions, the concentration of malonic dialdehyde in the liver increased by 1.71 times, the production of superoxide anion radical increased by 1.3 times, the concentration of peroxynitrite increased by 1.9 times, sulfide anion decreased by 2.11 times, while OMP in the liver of rats decreased by 1.98 times compared to chronic alcoholic hepatitis. Conclusion. Administration of doxorubicin against the background of chronic alcoholic hepatitis limits the oxidative modification of liver proteins and the production of nitric oxide from the inducible isoform of NO-synthase.