Experimental studies of the metabolic response of the organism to subchronic intoxication with diacetylguanine

Introduction. Amine-containing heterocyclic compounds are increasingly used in chemical and pharmaceutical production. A special place among them is occupied by the substances of the guanine derivative group, which have antiviral, antifungal, and cytoprotective biological effects. Thus, diacetylguanine is the starting raw material for the synthesis of the anti-tumor Thioguanine drug widely used in the complex leukemia therapy. A preventive measure on the risk avoidance of developing occupational intoxications during synthesis is knowledge of the body’s response to the use of chemical compounds.

The aim of the study. To investigate the features of the body metabolic response to sub-chronic intoxication with diacetylguanine in an experiment.

Materials and methods. We investigated N², N⁹⁽⁷⁾-diacetylguanine, an organic compound of a number of nitrogen-containing heterocycles. The body response to sub-chronic intoxication with diacetylguanine was studied on white male rats. The state of the animals was assessed by integral parameters, indices of peripheral blood and biochemical analysis of blood serum. The obtained results were processed using the Statistic 10.0 software.

Results. In the subchronic experiment, a toxic effect on hepatocytes was revealed: increased activity of AST, ALT, elevated total bilirubin, cholesterol, decreased total protein in the blood serum. Increased activity of α-amylase, indicating developing inflammation of the pancreas. Leukocytosis due to segmented neutrophils with relative lymphopenia and eosinophilia was noted in the peripheral blood. Adverse effects of diacetylguanine administration manifested themselves in disruption of basic physiological and, as a consequence, behavioural responses of the body: increased indices characterizing the ability of the nervous system to summarize subthreshold impulses, a reliable decrease in body temperature by 3.2–3.3 ˚C was noted and hypokinesia was detected in experimental animals. Electrocardiographic examination data revealed impaired atrio-ventricular conduction and slower excitation transmission through the ventricles.

Limitations. In vivo experiments conducted in accordance with the directive documents on the protection of experimental animals limit their number related to the ethical requirements for in vivo experiments.

Conclusion. The conducted experiment showed subchronic intake of diacetylguanine into the body to be a risk factor for the development of pathology, primarily of the hepatobiliary system. At the same time, clinically significant liver damage can be provoked even by small doses of the xenobiotic when entering the body over a long period. The experiment revealed a highly informative complex of biochemical indicators that correctly reflect signs of disturbances in the body’s condition upon contact with N², N⁹⁽⁷⁾-diacetylguanine, including: increased activity of ALT, AST, and alkaline phosphatase in the blood serum in combination with an increase in the concentration of urea and bilirubin, neutrophilic leukocytosis with relative lymphopenia in the peripheral blood.

Compliance with ethical standards. The study was approved by the local Ethics Committee of the Research Institute for Complex Problems of Hygiene and Occupational Diseases (Protocol of the Meeting No. 4 § 2 from 18.11.2021). The maintenance, feeding and withdrawal of animals from the experiment were carried out in accordance with the requirements of the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (ETS No. 123, Strasbourg, 18.03.1986).

Contribution:
Gorokhova L.G. – concept and design of the study, collection and processing of material, statistical processing, writing the text;
Mikhailova N.N. – writing the text, editing;
Gostyaeva E.P. – collection and processing of material, statistical processing;
Zhukova A.G. – collection and processing of material, statistical processing, writing the text.
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.

Acknowledgement. The study had no sponsorship.

Received: December 27, 2024 / Accepted: March 26, 2025 / Published: April 30, 2025

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