Time-Dependent Alterations in Liver Oxidative Stress due to Ethanol and Acetaldehyde
Main Article Content
Keywords
acetaldehyde, alcohol, antioxidant, apoptosis, mitochondria, oxidative stress
Abstract
Binge drinking is a major public health issue and ethanol-related liver insult may play a major role in the pathology of alcoholic liver disease. However, the degree of oxidative stress, cell death and contribution of acetaldehyde to liver damage over a 24-h period has yet to be determined. Herein, we aimed to investigate the effect of acute alcohol and elevated acetaldehyde levels on hepatic oxidative damage, apoptosis, and antioxidant enzyme activity over a 24-h period. Male Wistar rats were divided into four groups and animals were pre-injected (intraperitonially [i.p.]) with either saline (0.15 mol/L) or cyanamide (5-mmol/kg body weight), followed by either saline (0.15 mol/L) or ethanol (75-mmol/kg bodyweight). After 2.5, 6 and 24 h, hepatic cytosolic and mitochondrial fractions were analysed for indices of oxidative stress. At 2.5 h, cytosolic glutathione and malondialdehyde levels were significantly reduced and increased, respectively, with alcohol treatment. Caspase-3 activity and cytochrome c levels were increased with alcohol treatment at 24 h. The combination of cyanamide and alcohol treatment at 24 h led to a significant increase in serum alanine aminotransferase levels, and reduced albumin and total protein levels. Furthermore, glutathione peroxidase activity and glutathione reductase activity were significantly decreased and increased, respectively. Finally, superoxide dismutase activity was decreased in cytosol and increased in the mitochondria after cyanamide and ethanol treatment, respectively. This study indicates a complex differential effect of alcohol and acetaldehyde, whereby alcohol toxicity in the mitochondria takes place throughout the 24-h period, but raised acetaldehyde has a further detrimental effect on liver function.
References
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32. García-Ruiz C, Morales A, Ballesta A, Rodés J, Kaplowitz N, Fernández-Checa JC. Effect of chronic ethanol feed in gonglutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes. J Clin Invest. 1994;94:193–201. 10.1172/JCI117306
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34. Colell A, García-Ruiz C, Morales A, Ballesta A, Ookhtens M, Rodés J, et al. Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: Effect of membrane physical properties and S-adenosyl-L-methionine. Hepatology. 1997;26:699–708. 10.1053/jhep.1997.v26.pm0009303501
35. Cahill A, Cunningham CC, Adachi M, Ishii H, Bailey SM, Fromenty B, et al. Effects of alcohol and oxidative stress on liver pathology: The role of the mitochondrion. Alcohol Clin Exp Res. 2002 Jun;26(6):907–15. 10.1097/00000374-200206000-00022
36. Sriram KI, Lakshmi CJ. Endurance exercise-induced alterations in antioxidant enzymes of old albino male rats. Curr Sci. 2001;80(8):921–23.
37. Das SK, Vasudevan DM. Effect of ethanol on liver antioxidant defense systems: Adose-dependent study. Indian J Clin Biochem. 2005;20:80–84. 10.1007/BF02893047
38. Chandra R, Aneja R, Rewal C, Konduri R, Dass SK, Agarwal S. An opium alkaloid-papaverine ameliorates ethanol-induced hepatotoxicity: Diminution of oxidative stress. Indian J Clin Biochem. 2000;15:155–60. 10.1007/BF02883745
2. Osna NA, Donohue TM, Kharbanda KK. Alcoholic liver disease: Pathogenesis and current management. Alcohol Res. 2017;38:147–61. PMid: 28988570; PMCID: PMC5513682.
3. Cederbaum AI. Alcohol metabolism. Clin Liver Dis. 2012;16:667–85. 10.1016/j.cld.2012.08.002
4. Guo R, Jun R. Alcohol and acetaldehyde in public health: From marvel to menace. Int. J. Environ. Res. Public Health. 2010;7:1285–301. 10.3390/ijerph7041285
5. Tuma DJ. Role of malondialdehyde-acetaldehyde adducts in liver injury. Free Radic Biol Med. 2002;32:303–8. 10.1016/S0891-5849(01)00742-0
6. Niemelä O, Parkkila S, Juvonen RO, Viitala K, Gelboin HV., Pasanen M. Cytochromes P4502A6, 2E1, and 3A and production of protein-aldehyde adducts in the liver of patients with alcoholic and non-alcoholic liver diseases. J Hepatol. 2000;33:893–901. 10.1016/S0168-8278(00)80120-8
7. Garcia-Ruiz C, Fernandez-Checa JC. Mitochondrial glutathione: Hepatocellular survival–death switch. J Gastroenterol Hepatol. 2006;21:S3–S6. 10.1111/j.1440-1746.2006.04570.x
8. Lluis JM, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC. Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress. Gastroenterology. 2003;124:708–24. 10.1053/gast.2003.50089
9. Yan T, Zhao Y. Acetaldehyde induces phosphorylation of dynamin-related protein 1 and mitochondrial dysfunction via elevating intracellular ROS and Ca2+ levels. Redox Biol. 2020 Jan;28: 101381. 10.3389/fphar.2014.0015110.1016/j.redox.2019.101381
10. Pauly T, Dahmen N, Szegedi A, Wetzel H, Böl GF, Ferdinand K, et al. Blood ethanol levels and adenylyl cyclase activity in lymphocytes of alcoholic patients. Biol Psychiatry. 1999;45:489–93. 10.1016/S0006-3223(98)00075-4
11. Hillbom ME, Sarviharju MS, Lindros KO. Potentiation of ethanol toxicity by cyanamide in relation to acetaldehyde accumulation. Toxicol Appl Pharmacol. 1983;70:133–9. 10.1016/0041-008X(83)90186-2
12. Patel VB, Spencer CH, Young TA, Lively MO, Cunningham CC. Effects of 4-hydroxynonenal on mitochondrial 3-hydroxy-3-methylglutaryl (HMG-CoA) synthase. Free Radic Biol Med. 2007;43:1499–507. 10.1016/j.freeradbiomed.2007.08.004
13. Preedy VR, Gove CD, Panos MZ, Sherwood R, Portmann B, Williams R, et al. Liver histology, blood biochemistry and RNA, DNA and subcellular protein composition of various skeletal muscles of rats with experimental cirrhosis: Implications for alcoholic muscle disease. Alcohol Alcohol. 1990;25:641–9. 10.1093/oxfordjournals.alcalc.a045061
14. Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues. Anal Biochem. 1969;27:502–22. 10.1016/0003-2697(69)90064-5
15. Bar-Or D, Rael LT, Lau EP, Rao NKR, Thomas GW, Winkler JV, et al. Ananalog of the human albumin N-terminus (Asp-Ala-His-Lys) prevents formation of copper-induced reactive oxygen species. Biochem Biophys Res Commun. 2001;284:856–62. 10.1006/bbrc.2001.5042
16. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, et al. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 1990;186:464–78. 10.1016/0076-6879(90)86141-H
17. Petagine L, Zariwala MG, Patel VB. Alcoholic liver disease: Current insights into cellular mechanisms. World J Biol Chem. 2021;12:87–103. 10.4331/wjbc.v12.i5.87
18. Patel VB, Ajmal R, Sherwood RA, Sullivan A, Richardson PJ, Preedy VR. Cardioprotective effect of propranolol from alcohol-induced heart muscle damage as assessed by plasma cardiac troponin-T. Alcohol Clin Exp Res. 2001;25:882–9. 10.1111/j.1530-0277.2001.tb02294.x
19. Closon C, Didone V, Tirelli E, Quertemont E. Acetaldehyde and the hypothermic effects of ethanol in mice. Alcohol Clin Exp Res. 2009;33:2005–14. 10.1111/j.1530-0277.2009.01039.x
20. Morales-González JA, Sernas-Morales M de L, Morales-González Á, González-López LL, Madrigal-Santillán EO, Vargas-Mendoza N, et al. Morphological and biochemical effects of weekend alcohol consumption in rats: Role of concentration and gender. World J Hepatol. 2018;10:297–307. 10.4254/wjh.v10.i2.297
21. Lucas D, Ménez JF, Bodénez P, Baccino E, Bardou LG, Floch HH. Acetaldehyde adducts with haemoglobin: Determination of acetaldehyde released from haemoglobin by acid hydrolysis. Alcohol Alcohol. 1988;23:23–31. PMid: 3358820
22. Hong-Brown LQ, Frost RA, Lang CH. Alcohol impairs protein synthesis and degradation in cultured skeletal muscle cells. Alcohol Clin Exp Res. 2001;25:1373–82. 10.1111/j.1530-0277.2001.tb02361.x
23. Marway JS, Preedy VR. The acute effects of ethanol and acetaldehyde on the synthesis of mixed and contractile proteins of the jejunum. Alcohol Alcohol. 1995;30:211–17. PMid: 7662040.
24. Öner-Iyidogan Y, Gürdö lF, Öner P. The effects of acute melatonin and ethanol treatment on antioxidant enzyme activities in rat testes. Pharmacol Res. 2001;44:89–93. 10.1006/phrs.2001.0828
25. Bailey SM, Cunningham CC. Acute and chronic ethanol increases reactive oxygen species generation and decreases viability in fresh, isolated rat hepatocytes. Hepatology. 1998;28:1318–26. 10.1002/hep.510280521
26. Farfán Labonne BE, Gutiérrez M, Gómez-Quiroz LE, Konigsberg Fainstein M, Bucio L, Souza V, et al. Acetaldehyde-induced mitochondrial dysfunction sensitizes hepatocytes to oxidative damage. Cell Biol Toxicol. 2009;25:599–609. 10.1007/s10565-008-9115-5
27. Colel lA, Garcia-Ruiz C, Miranda M, Ardite E, Mari M, Morales A, et al. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology. 1998;115:1541–51. 10.1016/S0016-5085(98)70034-4
28. Matsumoto A, Ichiba M, Horita M, Yamashita Z, Takahashi T, Isse T, et al. Lack of aldehyde dehydrogenase ameliorates oxidative stress induced by single-dose ethanol administration in mouse liver. Alcohol. 2007;41:57–59. 10.1016/j.alcohol.2007.01.004
29. Heymann HM, Gardner AM, Gross ER. Aldehyde-induced DNA and protein adducts as biomarker tools for alcohol use disorder. Trends Mol Med. 2018;24:144. 10.1016/j.molmed.2017.12.003
30. Chen P, Hu M, Liu F, Yu H, Chen C. S-allyl-l-cysteine (SAC) protects hepatocytes from alcohol-induced apoptosis. FEBS Open Bio. 2019;9:1327–36. 10.1002/2211-5463.12684
31. Ribas V, García-Ruiz C, Fernández-Checa JC. Glutathione and mitochondria. Front Pharmacol. 2014;5:151. 10.3389/fphar.2014.00151
32. García-Ruiz C, Morales A, Ballesta A, Rodés J, Kaplowitz N, Fernández-Checa JC. Effect of chronic ethanol feed in gonglutathione and functional integrity of mitochondria in periportal and perivenous rat hepatocytes. J Clin Invest. 1994;94:193–201. 10.1172/JCI117306
33. Chen Y, Dong H, Thompson D, Shertzer H, Nebert D, Vasiliou V. Glutathione defense mechanism in liver injury: Insights from animal models. Food Chem Toxicol. 2013;60:38–44. 10.1016/j.fct.2013.07.008
34. Colell A, García-Ruiz C, Morales A, Ballesta A, Ookhtens M, Rodés J, et al. Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: Effect of membrane physical properties and S-adenosyl-L-methionine. Hepatology. 1997;26:699–708. 10.1053/jhep.1997.v26.pm0009303501
35. Cahill A, Cunningham CC, Adachi M, Ishii H, Bailey SM, Fromenty B, et al. Effects of alcohol and oxidative stress on liver pathology: The role of the mitochondrion. Alcohol Clin Exp Res. 2002 Jun;26(6):907–15. 10.1097/00000374-200206000-00022
36. Sriram KI, Lakshmi CJ. Endurance exercise-induced alterations in antioxidant enzymes of old albino male rats. Curr Sci. 2001;80(8):921–23.
37. Das SK, Vasudevan DM. Effect of ethanol on liver antioxidant defense systems: Adose-dependent study. Indian J Clin Biochem. 2005;20:80–84. 10.1007/BF02893047
38. Chandra R, Aneja R, Rewal C, Konduri R, Dass SK, Agarwal S. An opium alkaloid-papaverine ameliorates ethanol-induced hepatotoxicity: Diminution of oxidative stress. Indian J Clin Biochem. 2000;15:155–60. 10.1007/BF02883745
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May 11, 2022
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Time-Dependent Alterations in Liver Oxidative Stress due to Ethanol and Acetaldehyde. (2022). Journal of Renal and Hepatic Disorders, 6(1), 56-66. https://doi.org/10.15586/jrenhep.v6i1.143
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