Application of S-Substituted Pteridinefor Acute Hepatitis Treatment in Rats

Abstract

Liver disease is one of the most common medical problems in the world. Pharmacocorrection of these pathologies includes the use of drugs with antioxidant and hepatoprotective action, among which there are natural and synthetic sulfur‐containing compounds. However, many of the drugs have side effects and their application does not always correspond to the approaches of evidence‐based medicine. Therefore, today the urgent problem is the search for new effective substances with high metabolitotropic properties and high safety criteria. The aim of the work was in‐depth study of the hepatoprotective and antioxidant action of the new investigational ʺlead‐compoundʺ among pteridine S‐substituted (DCTP) under conditions of experimental tetrachloromethane hepatitis in rats in comparison with the reference drug ʺThiotriazolineʺ. Methods: The hepatoprotective effect of the compound was studied using the model of acute tetrachloromethane (CCl4) hepatitis in adult male Wistar rats. The levels of biochemical liver damage markers were estimated with spectrophotometric methods. Histological and immunohistochemical methods were used for determination of hepatocytes damage. Statistical processing of data was performed using the nonparametric Wilcox‐on‐Mann‐Whitney method. Results: The results of the studies showed that DCTP was superior to the reference drug Thiotriazoline in its effect on the level of AST, DC, Schiff bases and carbonylated proteins, markers of oxidative (Nrf2) and inflammatory (Lipocalin‐2) stress, as well as on animal survival. The results were confirmed by histological examination data, which showed regeneration of the hepatocyte membrane structure, reduction of the infiltrative, destructive and inflammatory process in the liver, reduction of the cytolytic process, stabilization and increase in the functional activity of the liver due to the administration of the study drug. The pharmacological effects of lead‐compound (DCTP) are probably associated with its structural similarity to tetrahydrofolic acid, which is an integral component of oxidation‐reduction processes and a participant in the biosynthesis of nitrogenous bases of nucleotides, amino acids. The obtained data indicate antioxidant and hepatoprotective properties of the studied “lead‐compound” from the pteridinethione group (DCTP). Conclusions: It was shown that the studied substance DCTP significantly reduces acute hepa‐totoxic effects caused by CCl4, as evidenced by a decrease in the level of lipid peroxida‐tion and prooxidant markers, normalization of liver biochemical markers, as well as regeneration of liver architecture, limitation of inflammatory effects, a decrease in Nrf2 and Lipocalin‐2 markers, and induction of liver antioxidant enzymes.