AGE-DEPENDENCE OF BIOCHEMICAL MANIFESTATIONS OF HEPATOTOXIC INJURY IN RAT EXPOSED TO XENOBIOTICS OF VARIOUS GENESIS
DOI:
https://doi.org/10.31861/biosystems2024.01.003Keywords:
alanine aminotransferase, aspartate aminotransferase, de Ritis coefficient, alkaline phosphatase, gamma-glutamyltransferas, bilirubin, acetaminophen, diquat, toxic injury, liverAbstract
Currently, the problem of liver diseases against the backdrop of the toxic effects of medicinal and industrial (herbicides) xenobiotics on the body is becoming increasingly relevant. The activation of compensatory mechanisms in response to the action of toxic agents – acetaminophen and/or diquat is closely related to age-specific features. Heightened focus on acetaminophen-induced injury is linked to the widespread use of this medication as an analgesic and antipyretic during pandemics of infectious and inflammatory diseases, especially under the conditions of warfare in Ukraine. In return, the widespread use of the herbicide diquat is accompanied by an increase in the registration of cases of diquat -induced acute poisoning.
The aim of study was to evaluation the biochemical parameters of the functional state of the liver of different-aged rats under conditions of acetaminophen- and diquat-induced toxic injury. Animals were divided into three age groups: adolescent (60 days), reproductive (150 days), and mature age rats (360 days). Acute toxic injury by acetaminophen was modeled by its oral administration through gastric intubation at a daily dose of 1250 mg/kg of the animal's body weight during the last 2 days of the experiment. Acute toxic damage by diquat was modeled by a single intragastric administration using a probe at a dose of 115.5 mg/kg of the animal's body weight. The functional state of the liver was assessed on an automatic biochemical analyzer NTI Biochem FC-120.
Acetaminophen intoxication led to an increase in the absolute liver mass indicator, organ index, changes in the macroscopic structure of the organ, increased serum activities of ALT and AST, total LDH, and a decrease in the De Ritis ratio amidst increased activities of ALP, GGT, and levels of total and indirect bilirubin in all age groups compared to the control. The most significant changes were observed in mature age animals (increase in ALT activity by 76%, AST by 56%, ALP by 51%, GGT by 51%, and a decrease in the De Ritis ratio by 47%). Under conditions of diquat-induced toxic injury, a slightly different trend and degree in manifestation of established changes are observed. A more pronounced hepatotoxic effect was registered in adolescent animals, manifested by the maximum increase in absolute liver mass by 26%, ALT activity by 71%, AST by 47%, ALP by 50%, Bili-T level by 69%. No statistically significant differences compared to the control and APAP-induced injury in the activity of total LDH and GGT upon administration of toxic doses of the herbicide diquat regardless of age category were observed.
Based on the experimental results, an age-related multidirectionality in the adverse effects of the medicinal xenobiotic acetaminophen and the industrial xenobiotic diquat on indicators of the morpho-functional state of the liver is observed. The most sensitive age group of animals to toxic injury by acetaminophen are rats of 360 days of age, while for diquat – 60 days of age.
References
Baranov, Y. S., Zemtsova, O. V. (2023). Problems of monitoring some xenobiotics in territories affected by military actions. In S. T. Omelchuk (Ed.), Ecological and Hygienic Problems of Human Life Activity: Proceedings of the Scientific and Practical Conference with International Participation (pp. 52–53). Kyiv, Ukraine: MVC "Medinform". [in Ukrainian].
Benzick, A. E., Reddy, S. L., Gupta, S., Rogers, L. K., Smith, C. V. (1994). Diquat- and acetaminophen-induced alterations of biliary efflux of iron in rats. Biochemical pharmacology, 47(11), 2079–2085. https://doi.org/10.1016/0006-2952(94)90084-1
Botros, M., Sikaris, K. A. (2013). The de ritis ratio: the test of time. The Clinical biochemist. Reviews, 34(3), 117–130.
Caparrotta, T. M., Antoine, D. J., Dear, J. W. (2018). Are some people at increased risk of paracetamol-induced liver injury? A critical review of the literature. European journal of clinical pharmacology, 74(2), 147–160. https://doi.org/10.1007/s00228-017-2356-6
Chidiac, A. S., Buckley, N. A., Noghrehchi, F., Cairns, R. (2023). Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease. Expert opinion on drug metabolism & toxicology, 19(5), 297–317. https://doi.org/10.1080/17425255.2023.2223959
Chorna, V. V., Podolian, V. M., Volkotrub, M. O., Dzonik, I. A., Syvak, V. M., Slobodian, V. V. (2023). Comparison of approaches to TCCS anesthesia and MOZ order 1122 in combat conditions at the prehospital stage. Perspektyvy ta Innovatsii Nauky. Pedagogika. Psyhologiya. Medytsyna, 8(26), 547–560. [in Ukrainian].
Comandatore, A., Franczak, M., Smolenski, R. T., Morelli, L., Peters, G. J., Giovannetti, E. (2022). Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers. Seminars in cancer biology, 86(Pt 2), 93–100. https://doi.org/10.1016/j.semcancer.2022.09.001
Contreras-Zentella, M. L., Hernández-Muñoz, R. (2016). Is Liver Enzyme Release Really Associated with Cell Necrosis Induced by Oxidant Stress?. Oxidative medicine and cellular longevity, 2016, 3529149. https://doi.org/10.1155/2016/3529149
Fisher, E. S., Curry, S. C. (2019). Evaluation and treatment of acetaminophen toxicity. Advances in pharmacology, 85, 263–272. https://doi.org/10.1016/bs.apha.2018.12.004
Galluzzo, V., Zazzara, M. B., Ciciarello, F., Tosato, M., Bizzarro, A., Paglionico, A., Varriano, V., Gremese, E., Calvani, R., Landi, F., Gemelli against COVID-19 Post-Acute Care Team (2023). Use of First-Line Oral Analgesics during and after COVID-19: Results from a Survey on a Sample of Italian 696 COVID-19 Survivors with Post-Acute Symptoms. Journal of clinical medicine, 12(8), 2992. https://doi.org/10.3390/jcm12082992
Ghasemi, A., Jeddi, S., Kashfi, K. (2021). The laboratory rat: Age and body weight matter. EXCLI journal, 20, 1431–1445. https://doi.org/10.17179/excli2021-4072
Ketsa, O. V., Makarchuk, S. S., Marchenko, M. M. (2022). Biochemical markers of the hepatobiliary system functional state in blood serum of rats under the action of sodium benzoate and ascorbic acid. Fiziol Zh, 68(6), 73–79. https://doi.org/10.15407/fz68.06.073 [in Ukrainian].
Kopylchuk, H. P., Nykolaichuk, I. M., Lylyk, I. S. (2020). Indexes of citrulline metabolism in rat liver under the toxic injury against the background of alimentary protein deficiency. Ukrainian Biochemical Journal, 92(1), 113–119. https://doi.org/10.15407/ubj92.01.113 [in Ukrainian].
Lowe, D., Sanvictores, T., Zubair, M., John, S. (2024). Alkaline phosphatase. In StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK459201/
Magalhães, N., Carvalho, F., Dinis-Oliveira, R. J. (2018). Human and experimental toxicology of diquat poisoning: Toxicokinetics, mechanisms of toxicity, clinical features, and treatment. Human & experimental toxicology, 37(11), 1131–1160. https://doi.org/10.1177/0960327118765330
Mast, C., Dardevet, D., Papet, I. (2018). Impact of medication on protein and amino acid metabolism in the elderly: the sulfur amino acid and paracetamol case. Nutrition research reviews, 31(2), 179–192. https://doi.org/10.1017/S0954422418000021
Petersen, K. F., Dufour, S., Cline, G. W., & Shulman, G. I. (2019). Regulation of hepatic mitochondrial oxidation by glucose-alanine cycling during starvation in humans. The Journal of clinical investigation, 129(11), 4671–4675. https://doi.org/10.1172/JCI129913
Puukka, K., Hietala, J., Koivisto, H., Anttila, P., Bloigu, R., Niemelä, O. (2006). Additive effects of moderate drinking and obesity on serum gamma-glutamyl transferase activity. The American journal of clinical nutrition, 83(6), 1351–1449. https://doi.org/10.1093/ajcn/83.6.1351
Sewalk, C. J., Brewer, G. L., Hoffman, D. J. (2001). Effects of diquat, an aquatic herbicide, on the development of mallard embryos. Journal of toxicology and environmental health. Part A, 62(1), 33–45. https://doi.org/10.1080/00984100050201659
Sharma, A., Kumar, V., Shahzad, B., Tanveer, M., Sidhu, G. P., Handa, N., Kohli, S. K., Yadav, P., Bali, A. S., Parihar, R. D., Dar, O. I., Singh, K., Jasrotia, S., Bakshi, P., Ramakrishnan, M., Kumar, S., Bhardwaj, R., Thukral, A. K. (2019). Worldwide pesticide usage and its impacts on ecosystem. SN Applied Sciences, 1(11), 1446. https://doi.org/10.1007/s42452-019-1485-1
Siqueira, I. R., Vanzin, S. I., Tramontina, A. C., Bianchetti, P., Sbaraini, S., Almeida, L. M. V., Stulp, S., Perry, M. L. S., Gonçalves, C. A. S., Feoli, A. M. (2019). Potential susceptibility to liver dysfunction induced by a therapeutic dose of acetaminophen in rats submitted to gestational and lactational protein malnutrition. International Journal of Nutrition Sciences, 4(1), 1028.
Sun, Y. Q., Yuan, L., Gao, H. B., Yao, D. Q., Chen, Q. S., Tian, Y. P. (2019). Establishment and evaluation of acute diquat poisoning model in Wistar rats. Chinese journal of industrial hygiene and occupational diseases, 37(5), 342–346. https://doi.org/10.3760/cma.j.issn.1001-9391.2019.05.005
Teshayev M. (2023). Xenobiotics and their types. European journal of modern medicine and practice, 3(10), 14–17.
Wolkoff, A. W. (2014). Bilirubin metabolism. In J. F. Reinus, D. Simon (Eds.), Gastrointestinal Anatomy and Physiology (Chapter 12, pp. 17-82). http://dx.doi.org/10.1002/9781118833001.ch12
Wu, Y., Cui, S., Wang, W., Jian, T., Kan, B., Jian, X. (2022). Kidney and lung injury in rats following acute diquat exposure. Experimental and therapeutic medicine, 23(4), 275. https://doi.org/10.3892/etm.2022.11201
Zhou, W., He, H., Wei, Q., Che, L., Zhao, X., Liu, W., Yan, Y., Hu, L., Du, Y., Yin, Z., Shuai, Y., Yang, L., Feng, R. (2023). Puerarin protects against acetaminophen-induced oxidative damage in liver through activation of the Keap1/Nrf2 signaling pathway. Food science & nutrition, 11(10), 6604–6615. https://doi.org/10.1002/fsn3.3609
