CHANGE OF THE PROFILE OF EXPRESSION OF ADAPTIVE RESPONSE GENES IN TOXIC HEPATITIS OF DIFFERENT ETIOLOGY
Introduction. In Russia, the problem of toxic hepatitis is of great importance and relevance. The etiology of toxic hepatitis (industrial toxicants, drugs, ethanol) and, as a consequence, pathogenesis may have significant differences at the molecular genetic level. The aim of the study was to analyze the expression of genes involved in the response to toxic liver damage of various etiologies. Material and methods. Toxic hepatitis was modulated in male albino mongrel rats weighing 180-200 grams assigned to four groups (control group, carbon tetrachloride, paracetamol, ethanol). After 24 and 72 hours of paracetamol administration, rats were anesthetized and the mRNA levels of the Chek1, Gclc, Gstm1, Gstp1, Gstt1, Nfe2l2, Nqo1, Ripk1 genes in the liver homogenate were examined. Results. As a result of the analysis of the genes expression studied, the expression profile was found TO be differed depending on the etiology of toxic hepatitis. With carbon tetrachloride poisoning, an increase in the expression of the Nqo1 genes (p = 0.001), Gstm1 (p = 0.037) and a decrease in the expression of the Nfe2l2 genes (p = 0.004), Ripk1 (p = 0.004) was observed. With the liver damage by paracetamol and its metabolites, opposite to the expression of the Gstm1 gene (p = 0.001) decreased, and the expression of the Nfe2l2 (p = 0.009), Gclc (p = 0.001), Chek1 (p = 0.011) genes increased. During alcohol intoxication, there were no statistically significant changes in the expression profiles of the genes studied. Conclusion. the results obtained may indicate the involvement of various molecular genetic mechanisms in the process of response to toxic liver damage, depending on the etiology.
About the authorsKarimov Denis O.
Khoury T., Rmeileh A.A., Yosha L., Benson A.A., Daher S., Mizrahi M. Drug Induced Liver Injury: Review with a Focus on Genetic Factors, Tissue Diagnosis, and Treatment Options. J Clin Transl Hepatol. 2015; 3 (2): 99-108.
Oh I.S., Park S.H. Immune-mediated Liver Injury in Hepatitis B Virus Infection. Immune Netw. 2015; 15 (4): 191-8.
Ren F., Zhang L., Zhang X., Shi H., Wen T., Bai L. et al. Inhibition of glycogen synthase kinase 3β promotes autophagy to protect mice from acute liver failure mediated by peroxisome proliferator-activated receptor α. Cell Death Dis. 2016; 7: e2151.
Nelson S.D. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis. 1990; 10: 267-78. DOI: 10.1055/s-2008-1040482.
Bessems J.G., Vermeulen N.P. Paracetamol (acetaminophen)-induced toxicity: Molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol. 2001; 31: 55-138. DOI: 10.1080/20014091111677.
Kon K., Kim J.S., Jaeschke H., Lemasters J.J. Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology. 2004; 40: 1170-9. DOI: 10.1002/hep.20437.
Cover C., Mansouri A., Knight T.R., Bajt M.L., Lemasters J.J., Pessayre D. et al. Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther. 2005; 315: 879-87. DOI: 10.1124/jpet.105.088898.
Jaeschke H., McGill M.R., Ramachandran A. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev. 2012; 44: 88-106. DOI: 10.3109/03602532.2011.602688.
Kim H.Y., Kim J.K., Choi J.H., Jung J.Y., Oh W.Y., Kim D.C. et al. Hepatoprotective effect of pinoresinol on carbon tetrachloride-induced hepatic damage in mice. J Pharmacol Sci. 2010; 112: 105-12.
Allman M., Gaskin L., Rivera C.A. CCl4-induced hepatic injury in mice fed a Western diet is associated with blunted healing. J Gastroenterol Hepatol. 2010; 25: 635-43.
Ma X., Xu L., Wang S., Chen H., Xu J., Li X. et al. Loss of steroid receptor co-activator-3 attenuates carbon tetrachloride-induced murine hepatic injury and fibrosis. Lab Invest. 2009; 89: 903-14.
Bajt M.L., Cover C., Lemasters J.J., Jaeschke H. Nuclear translocation of endonuclease G and apoptosis-inducing factor during acetaminophen-induced liver cell injury. Toxicol Sci. 2006; 94: 217-25. DOI: 10.1093/toxsci/kfl077.
Berg J.M., Tymoczko J.L. In: Freeman W. Biochemistry. New York; 2002. Section 30.5, Ethanol Alters Energy Metabolism in the Liver.
Friel P.N., Baer J.S., Logan B.K. Variability of ethanol absorption and breath concentrations during a large-scale alcohol administration study. Alcohol Clin Exp Res. 1995; 19: 1055-60.
Viitala K., Makkonen K., Israel Y., Lehtimäki T., Jaakkola O., Koivula T. et al. Autoimmune responses against oxidant stress and acetaldehyde-derived epitopes in human alcohol consumers. Alcohol Clin Exp Res. 2000; 24: 1103-9.
Tuma D.J., Casey C.A. Dangerous byproducts of alcohol breakdown-focus on adducts. Alcohol Res Health. 2003; 27: 285-90.
Chayanupatkul M., Liangpunsakul S. Alcoholic hepatitis: a comprehensive review of pathogenesis and treatment. World J Gastroenterol. 2014; 20: 6279-86.
Itoh K., Igarashi K., Hayashi N., Nishizawa M., Yamamoto M. Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. Mol Cell Biol. 1995; 15: 4184-93.
Moi P., Chan K., Asunis I., Cao A., Kan Y.W. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA. 1994; 91: 9926-30.
Hayes J.D., Dinkova-Kostova A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci. 2014; 39: 199-218.
Tait S.W., Green D.R. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010; 11 (9): 621-32. DOI: 10.1038/nrm2952.
Liu Q., Guntuku S., Cui X.S., Matsuoka S., Cortez D., Tamai K. et al. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000; 14: 1448-59.
Chen L., Chao S.B., Wang Z.B., Qi S.T., Zhu X.L., Yang S.W. et al. Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes. Cell Cycle. 2012; 11 (10): 1948-55.
Rinaldi V.D., Bolcun-Filas E., Kogo H., Kurahashi H., Schimenti J.C. The DNA damage checkpoint eliminates mouse oocytes with chromosome synapsis failure. Mol Cell. 2017; 67 (6): 1026-36.e2.
Berger S.B. et al. Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J Immunol. 2014; 192: 5476-80. DOI: 10.4049/jimmunol.1400499.
Polykratis A. et al. Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J Immunol. 2014; 193: 1539-43. DOI: 10.4049/jimmunol.1400590.
Kensler T.W., Wakabayashi N., Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007; 47: 89-116. Epub 2006/09/14. 10.1146/annurev.pharmtox.46.120604.141046.
Itoh K., Chiba T., Takahashi S., Ishii T., Igarashi K., Katoh Y. et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997; 236 (2): 313-22. Epub 1997/07/18.
Kalinina E.V., Chernov N.N., Novichkova M.D. The role of glutathione, glutathione transferase and glutaredoxin in the regulation of redox-dependent processes. Uspekhi biologichkoy khimii. 2014; 54: 299-348. (in Russian)
- Refbacks are not listed
Контент доступен под лицензией Creative Commons Attribution 3.0 License.