Introduction. It is well recognized that drug metabolism products in the liver can induce oxidative stress and mitochondrial dysfunction, leading to the development of hepatocellular injury. As a potential agent capable of counteracting the hepatotoxic effects of drugs, we focused our attention on a domestic biotechnological preparation – cryopreserved placental extract (CPE).
The aim. To characterize gender differences in the effect of esomeprazole, clarithromycin, metronidazole (E/C/M), and CPE on the intensity of lipid peroxidation and the activity of the antioxidant system in tetrachloromethane (CCl4) hepatitis with a background of ethanol-induced cirrhosis (ETCM).
Materials and methods. The study was conducted with varying levels of sex hormones on 112 male and female rats. Chronic ETCM was induced by administering a 50.0% oil solution of CCl4 at a dose of 8 ml/kg body weight of the animals twice a week, in combination with a 5.0% ethanol solution for drinking over a period of 45 days. The content of TBA-RP in liver homogenates was determined spectrophotometrically by the method described by Asakawa T. et al. Catalase activity in liver homogenates was determined spectrophotometrically according to the method of Korolyuk M.A. and co-authors.
Results. The most pronounced increase in lipid peroxidation processes was observed in females with chronic ETCM-induced liver damage and administration of antiulcer drugs following ovariectomy, resulting in a TBA-RS content of 36.1±2.79 μmol/kg of tissue. Administration of E/C/M in animals with chronic liver damage led to a suppression of the antioxidant system, as evidenced by a decrease in catalase activity in liver tissues.
Conclusion. The combined use of anti-ulcer drugs and CPE on the background of chronic ETCM mitigated the activation of lipid peroxidation processes, which was indicated by a statistically significant (p < 0.001) 2.7-fold lower content of TBA-RP in liver homogenates. Additionally, it was established that the administration of CPE was accompanied by a statistically significant increase in catalase activity in females, more prominently than in males. In females without changes in hormonal status, the introduction of CPE resulted in a growth (p < 0.001) of catalase activity by 75.0%, with the most significant increase observed in females after ovariectomy – catalase activity statistically significantly (p < 0.001) increased by 2.6 times compared to the indicators of females not administered with CPE. The administration of CPE in female rats without altering hormonal status was accompanied by a twofold (p < 0.01) increase in the antioxidant-prooxidant index compared to male rats, indicating more pronounced antioxidant properties of CPE in female rats.
Wei, L, Ding, H. G. (2021). Helicobacter pylori infection and peptic ulcer disease in cirrhotic patients: An updated meta-analysis. World Journal of Clinical Cases. 9 (24), 7073–7084. https://doi.org/10.12998/wjcc.v9.i24.7073
Leontiadis, G. I., Molloy-Bland, M., Moayyedi, P., Howden, C. W. (2013). Effect of comorbidity on mortality in patients with peptic ulcer bleeding: systematic review and meta-analysis. The American Journal of Gastroenterology, 108 (3), 331–345. https://doi.org/10.1038/ajg.2012.451
Malfertheiner, P., Megraud, F., Morain, C. A., Gisbert, J. P., Kuipers, E. J., Axon A. T., Bazzoli, F., et al. (2017). European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection-the Maastricht V / Florence Consensus Report. Gut, 66 (1), 6–30. https://doi.org/10.1136/gutjnl-2016-312288
Koshurba, I. V., Hladkykh, F. V., Chyzh, M. O. (2023). Modern approaches to the treatment of peptic ulcer disease and prospects for the use of biological therapy. Modern Medical Technology, 2 (57), 58–66. https://doi.org/10.34287/MMT.2(57).2023.10
Hladkykh, F. V., Kulinich, Н. V., Zolotarova, T. G. (2023). New approaches to radio- and chemosensitization using proton pump inhibitors through the lens of tumor cell microenvironment patterns. Ukrainian journal of radiology and oncology. 31 (2), 230–242. DOI: https://doi.org/10.46879/ukroj.2.2023.230-242
Kancherla, D., Gajendran, M., Vallabhaneni, P., Vipperla, K. (2013). Metronidazole induced liver injury: a rare immune mediated drug reaction. Case Reports in Gastrointestinal Medicine, 568193. https://doi.org/10.1155/2013/568193
Zeng, Y., Dai, Y., Zhou, Z., Yu, X., Shi, D. Hepatotoxicity-Related Adverse Effects of Proton Pump Inhibitors: A Cross-Sectional Study of Signal Mining and Analysis of the FDA Adverse Event Report System Database. Frontiers in Medicine (Lausanne). 2021;8:648164. https://doi.org/10.3389/fmed.2021.648164
Paz, M. F., Alencar, M. V., Lima, R. M., Sobral, A. L., Nascimento, G. T., Dos Reis, C. A., Coеlho, M. D.P., et al. (2020). Pharmacological effects and toxicogenetic impacts of omeprazole: genomic instability and cancer. Oxidative Medicine and Cellular Longevity, 2020, 3457890. https://doi.org/10.1155/2020/3457890
Waxman, D. J., Holloway, M. G. (2009). Sex differences in the expression of hepatic drug metabolizing enzymes. Molecular Pharmacology, 76 (2), 215–228. https://doi.org/10.1124/mol.109.056705
Koshurba, I. Vю, Hladkykh, F. V., Chyzh, M. O. (2022). Modulation of lipid peroxidation and energy metabolism in the gastric mucosa as a mechanism of antiulcer activity of placental cryoextract in the healing of stress-induced ulcers. Gastroenterology, 56 (3), 149–155. https://doi.org/10.22141/2308-2097.56.3.2022.503
Hladkykh, F. V., Koshurba, I. V., Chyzh, M. O. (2023) Characteristics of the antiulcerogenic activity of cryopreserved placenta extract in acute and chronic lesions of the stomach. Modern Medical Technology, 56 (1), 62–68. https://doi.org/10.34287/MMT.1(56).2023.10
Pan, S. Y., Chan, M. K., Wong, M. B., Klokol, D., Chernykh, V. (2017). Placental therapy: An insight to their biological and therapeutic properties. Journal of Medicine and Therapeutics, 1 (3), 1–6. https://doi.org/10.15761/JMT.1000118
Vogel H. G. ed. Drug Discovery and Evaluation: Pharmacological Assays Berlin, Heidelberg: Springer Berlin Heidelberg 2008. 2071 p.
Stefanov, O. V. (2001). Preclinical studies of drugs: guidelines. Kyiv: Avicenna, 527 p.
Podhirny, V. V. (2007). Hepatotoxic manifestations of lansoprazole, metronidazole and clarithromycin in the experiment. Medicinal Chemistry, 9 (2), 74–77.
Koshurba, I. V., Chyzh, M. O., Hladkykh, F. V. (2022). Influence of placenta cryoextract on the liver metabolic and functional state in case of D-galactosamine hepatitis. Innovative Biosystems and Bioengineering, 6 (2), 64–74. https://doi.org/10.20535/ibb.2022.6.2.264774
Rykalo, N. A. (2009) Experimental model of chronic tetrachloromethane hepatitis and liver cirrhosis in immature rats. Actual problems of modern medicine: Bulletin of the Ukrainian Medical Stomatological Academy, 9 (2), 116–118.
Aloisi, A. M., Ceccarelli, I., Fiorenzani, P. (2003). Gonadectomy affects hormonal and behavioral responses to repetitive nociceptive stimulation in male rats. Annals of the New York Academy of Sciences, 1007, 232–237. https://doi.org/10.1196/annals.1286.022
Joshi, S. A., Shaikh, S., Ranpura, S., Khole, V. V. (2003). Postnatal development and testosterone dependence of a rat epididymal protein identified by neonatal tolerization. Reproduction, 125 (4), 3495–3507. https://doi.org/10.1530/rep.0.1250495
Ali, B. H., Ben Ismail, T. H., Basir, A. A. (2001) Sex difference in the suspectibility of rats to gentamicin nephrotoxicity: influence of gonadectomy and hormonal replacement therapy. Indian Journal of Pharmacology, 33, 369–373.
Koshurba, I. V., Chyzh, M. O., Hladkykh, F. V., Komorovskyi, R. R., Marchenko, M.M. (2023). Role of cryopreserved placenta extract in prevention and treatment of paracetamol-induced hepatotoxicity in rats. Scripta Medica, 54 (2), 133–139. http://doi.org/10.5937/scriptamed54-44663
Chyzh, M. O., Koshurba, I. V., Marchenko, M. M., Hladkykh, F. V., Belochkina, I. V. (2023). Gender determinism of the effect of placenta cryoextract on the hepatotropic effects of esomeprazole, clarithromycin and metronidazole in chronic liver damage. Modern Medical Technology, 56 (1): 55–61. https://doi.org/10.34287/MMT.1(56).2023.9
Koshurba, I. V., Hladkykh, F. V., Chyzh, M. O. (2023). The influence of hormonal status on the hepatotropic effect of esomeprazole, clarithromycin and metronidazole in chronic liver damage and the administration of placenta cryoextract. Gastroenterology, 57 (2), 78–84. https://doi.org/10.22141/2308-2097.57.2.2023.535
Asakawa, T., Matsushita, S. (1980). coloring condition of thiobarbituric acid test for detecting lipid hydroperoxides. Lipids, 15 (3), 137–140.
Korolyuk, M. A., Ivanova, L. K., Mayorova, I. G., Tokareva, V. A. (1988). Method For The Determination of Catalase Activity. Clinical laboratory diagnosis, 4, 44–47.
Kamyshnikov, V. S. (2009). Handbook of clinical and biochemical research and laboratory diagnostics. MEDpress-inform, 896 p.
Zar, J. H. (2014). Biostatistical analysis (5 ed.). Prentice-Hall, Englewood, 960 р.
Raskovic, A., Milanovic, I., Pavlovic, N., Cebovic, T., Vukmirovic, S., Mikov, M. (2014). Antioxidant activity of rosemary (Rosmarinus officinalis L.) essential oil and its hepatoprotective potential. BMC Complementary Medicine and Therapies, 14, 225. https://doi.org/10.1186/1472-6882-14-225
Gu, X., Manautou, J. E. (2012). Molecular mechanisms underlying chemical liver injury. Expert Reviews in Molecular Medicine, 14, e4. https://doi.org/10.1017/S1462399411002110
Tanikawa, K., Torimura, T. (2006). Studies on oxidative stress in liver diseases: important future trends in liver research. Medical Molecular Morphology, 39 (1), 22–27. https://doi.org/10.1007/s00795-006-0313-z
Zhu, R., Wang, Y., Zhang, L., Guo, Q. (2012). Oxidative stress and liver disease. Hepatology Research, 42 (8), 741–749. https://doi.org/10.1111/j.1872-034X.2012.00996.x
Almazroo, O. A., Miah, M. K., Venkataramanan R. (2017). Drug Metabolism in the Liver. Clinical Liver Disease, 21, 1–20. http://dx.doi.org/10.1016/j.cld.2016.08.001
Koshurba, I. V., Hladkykh, F. V., Chyzh, M. O., Belochkina, I. V., Rubleva, T. V. (2022). Hepatotropic effects of triple antiulcer therapy and placenta cryoextract: the role of sex factors in lipoperoxidation. Fiziolohichnyi zhurnal, 68 (5), 25–32. https://doi.org/10.15407/fz68.05.025
Zivna, H., Zivny, P., Vokurkova, D., Svejkovska, K., Palicka, V. (2010). The effect of chronic iron losses on liver regeneration in male and female rats. Biomedical papers of the Medical Faculty of the University Palacky, 154 (2), 153–158. https://doi.org/10.5507/bp.2010.023
Thorgersen, E. B., Barratt-Due, A., Haugaa, H., Harboe, M., Pischke, S. E., Nilsson, P. H., et al. (2019). The role of complement in liver injury, regeneration, and transplantation. Hepatology, 70 (2), 725–736. https://doi.org/10.1002/hep.30508
Forbes, S. J., Newsome, P. N. (2016). Liver regeneration – mechanisms and models to clinical application. Nature Reviews Gastroenterology & Hepatology, 13 (8), 473–485. https://doi.org/10.1038/nrgastro.2016.97
Hladkykh F. V., Belochkina I. V., Koshurba I. V., Chyzh M. O. (2023). Modern hepatoprotection: a narrative review of existing approaches and prospects for the use of biotechnological drugs. Modern Medical Technology, 3 (58), 58–65. https://doi.org/10.34287/MMT.3(55).2023.9
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.