Browse > Article
http://dx.doi.org/10.4062/biomolther.2020.108

Ibuprofen Increases the Hepatotoxicity of Ethanol through Potentiating Oxidative Stress  

Kim, Minjeong (College of Pharmacy, Ewha Womans University)
Lee, Eugenia Jin (Department of Biological Sciences, Columbia College, Columbia University)
Lim, Kyung-Min (College of Pharmacy, Ewha Womans University)
Publication Information
Biomolecules & Therapeutics / v.29, no.2, 2021 , pp. 205-210 More about this Journal
Abstract
Over 30 million prescriptions of NSAIDs (non-steroidal anti-inflammatory drugs) are issued every year. Considering that these drugs are available without a prescription as over the counter (OTC) drugs, their use will be astronomical. With the increasing use of NSAIDs, their adverse effects are drawing attention. Especially, stomach bleeding, kidney toxicity, liver toxicity, and neurological toxicity are reported as common. Ibuprofen, one of the extensively used NSAIDs along with aspirin, can also induce liver toxicity, but few studies are addressing this point. Here we examined the liver toxicity of ibuprofen and investigated whether co-exposure to ethanol can manifest synergistic effects. We employed 2D and 3D cultured human hepatoma cells, HepG2 to examine the synergistic hepatotoxicity of ibuprofen and alcohol concerning cell viability, morphology, and histology of 3D spheroids. As a result, ibuprofen and alcohol provoked synergistic hepatotoxicity against hepatocytes, and their toxicity increased prominently in 3D culture upon extended exposure. Oxidative stress appeared to be the mechanisms underlying the synergistic toxicity of ibuprofen and alcohol as evidenced by increased production of ROS and expression of the endogenous antioxidant system. Collectively, this study has demonstrated that ibuprofen and EtOH can induce synergistic hepatotoxicity, providing a line of evidence for caution against the use of ibuprofen in combination with alcohol.
Keywords
Ibuprofen; Alcohol; Hepatotoxicity; HepG2; 3D spheroid; Oxidative stress;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Mattson, M. P. and Camandola, S. (2001) NF-κB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107, 247-254.   DOI
2 McGill, M. R. and Jaeschke, H. (2013) Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis. Pharm. Res. 30, 2174-2187.   DOI
3 Prescott, L. F. (2000) Paracetamol, alcohol and the liver. Br. J. Clin. Pharmacol. 49, 291-301.   DOI
4 Riley, T. R. and Smith, J. P. (1998) Ibuprofen-induced hepatotoxicity in patients with chronic hepatitis C: a case series. Am. J. Gastroenterol. 93, 1563-1565.   DOI
5 Riordan, S. M. and Williams, R. (2002) Alcohol exposure and paracetamol-induced hepatotoxicity. Addict. Biol. 7, 191-206.   DOI
6 Sanchez-Valle, V., Chavez-Tapia, N. C., Uribe, M. and Mendez-Sanchez, N. (2012) Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr. Med. Chem. 19, 4850-4860.   DOI
7 Slattery, J. T., Nelson, S. D. and Thummel, K. E. (1996) The complex interaction between ethanol and acetaminophen. Clin. Pharmacol. Ther. 60, 241-246.   DOI
8 Sooklert, K., Wongjarupong, A., Cherdchom, S., Wongjarupong, N., Jindatip, D., Phungnoi, Y., Rojanathanes, R. and Sereemaspun, A. (2019) Molecular and morphological evidence of hepatotoxicity after silver nanoparticle exposure: a systematic review, in silico, and ultrastructure investigation. Toxicol. Res. 35, 257-270.   DOI
9 Stark, L. A., Reid, K., Sansom, O. J., Din, F. V., Guichard, S., Mayer, I., Jodrell, D. I., Clarke, A. R. and Dunlop, M. G. (2007) Aspirin activates the NF-κB signalling pathway and induces apoptosis in intestinal neoplasia in two in vivo models of human colorectal cancer. Carcinogenesis 28, 968-976.   DOI
10 Tolman, K. G. (1998) Hepatotoxicity of non-narcotic analgesics. Am. J. Med. 105, 13S-19S.   DOI
11 Toyokuni, S., Okamoto, K., Yodoi, J. and Hiai, H. (1995) Persistent oxidative stress in cancer. FEBS Lett. 358, 1-3.   DOI
12 Zhen, A. X., Piao, M. J., Kang, K. A., Fernando, P., Kang, H. K., Koh, Y. S., Yi, J. M. and Hyun, J. W. (2019) Niacinamide protects skin cells from oxidative stress induced by particulate matter. Biomol. Ther. (Seoul), 27, 562-569.   DOI
13 Zhong, Z., Ramshesh, V. K., Rehman, H., Liu, Q., Theruvath, T. P., Krishnasamy, Y. and Lemasters, J. J. (2014) Acute ethanol causes hepatic mitochondrial depolarization in mice: role of ethanol metabolism. PLoS ONE 9, e91308.   DOI
14 Bessone, F. (2010) Non-steroidal anti-inflammatory drugs: what is the actual risk of liver damage? World J. Gastroenterol. 16, 5651-5661.   DOI
15 Agency for Healthcare Research and Quality (AHRQ) (2016) Ibuprofen Drug Usage Statistics, United States, 2005-2015.
16 Aithal, G. P. and Day, C. P. (2007) Nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Clin. Liver Dis. 11, 563-575.   DOI
17 Bang, C. Y., Byun, J. H., Choi, H. K., Choi, J. S. and Choung, S. Y. (2016) Protective effects of Ecklonia stolonifera extract on ethanolinduced fatty liver in rats. Biomol. Ther. (Seoul) 24, 650-658.   DOI
18 Boureau, F., Schneid, H., Zeghari, N., Wall, R. and Bourgeois, P. (2004) The IPSO study: ibuprofen, paracetamol study in osteoarthritis. A randomised comparative clinical study comparing the efficacy and safety of ibuprofen and paracetamol analgesic treatment of osteoarthritis of the knee or hip. Ann. Rheum. Dis. 63, 1028-1034.   DOI
19 Chang, S. Y., Li, W., Traeger, S. C., Wang, B., Cui, D., Zhang, H., Wen, B. and Rodrigues, A. D. (2008) Confirmation that cytochrome P450 2C8 (CYP2C8) plays a minor role in (S)-(+)- and (R)-(-)-ibuprofen hydroxylation in vitro. Drug Metab. Dispos. 36, 2513-2522.   DOI
20 Cardile, S., Martinelli, M., Barabino, A., Gandullia, P., Oliva, S., Di Nardo, G., Dall'Oglio, L., Rea, F., de'Angelis, G. L., Bizzarri, B., Guariso, G., Masci, E., Staiano, A., Miele, E. and Romano, C. (2016) Italian survey on non-steroidal anti-inflammatory drugs and gastrointestinal bleeding in children. World J. Gastroenterol. 22, 1877-1883.   DOI
21 Edmondson, R., Broglie, J. J., Adcock, A. F. and Yang, L. (2014) Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev. Technol. 12, 207-218.   DOI
22 Flora, S. J. (2009) Structural, chemical and biological aspects of antioxidants for strategies against metal and metalloid exposure. Oxid. Med. Cell. Longev. 2, 191-206.   DOI
23 Freytag, A., Quinzler, R., Freitag, M., Bickel, H., Fuchs, A., Hansen, H., Hoefels, S., Konig, H. H., Mergenthal, K., Riedel-Heller, S. G., Schon, G., Weyerer, S., Wegscheider, K., Scherer, M., van den Bussche, H., Haefeli, W. E. and Gensichen, J. (2014) Use and potential risks of over-the-counter analgesics. Schmerz 28, 175-182.   DOI
24 Garcia Rodriguez, L. A., Williams, R., Derby, L. E., Dean, A. D. and Jick, H. (1994) Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch. Intern. Med. 154, 311-316.   DOI
25 Ghosh, R., Alajbegovic, A. and Gomes, A. V. (2015) NSAIDs and cardiovascular diseases: role of reactive oxygen species. Oxid. Med. Cell. Longev. 2015, 536962.   DOI
26 Giordano, F. J. (2005) Oxygen, oxidative stress, hypoxia, and heart failure. J. Clin. Invest. 115, 500-508.   DOI
27 Jana, N. R. (2008) NSAIDs and apoptosis. Cell. Mol. Life Sci. 65, 1295-1301.   DOI
28 Goldkind, L. and Laine, L. (2006) A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience. Pharmacoepidemiol. Drug Saf. 15, 213-220.   DOI
29 Grant, S., Millar, K. and Kenny, G. (2000) Blood alcohol concentration and psychomotor effects. Br. J. Anaesth. 85, 401-406.   DOI
30 Ha, H. L., Shin, H. J., Feitelson, M. A. and Yu, D. Y. (2010) Oxidative stress and antioxidants in hepatic pathogenesis. World J. Gastroenterol. 16, 6035-6043.   DOI
31 Janssen, G. and Venema, J. (1985) Ibuprofen: plasma concentrations in man. J. Int. Med. Res. 13, 68-73.   DOI
32 Joo, K. M., Kim, S., Koo, Y. J., Lee, M., Lee, S. H., Choi, D. and Lim, K. M. (2019) Development and validation of UPLC method for WST-1 cell viability assay and its application to MCTT HCETM eye irritation test for colorful substances. Toxicol. In Vitro 60, 412-419.   DOI
33 Jurima-Romet, M., Crawford, K. and Huang, H. S. (1994) Comparative cytotoxicity of non-steroidal anti-inflammatory drugs in primary cultures of rat hepatocytes. Toxicol. In Vitro 8, 55-66.   DOI
34 Kim, M., Lee, C. S. and Lim, K. M. (2019) Rhododenol activates melanocytes and induces morphological alteration at sub-cytotoxic levels. Int. J. Mol. Sci. 20, 5665.   DOI
35 Lieber, C. S. (1990) Mechanism of ethanol induced hepatic injury. Pharmacol. Ther. 46, 1-41.   DOI
36 Mates, J. M., Perez-Gomez, C. and Nunez de Castro, I. (1999) Antioxidant enzymes and human diseases. Clin. Biochem. 32, 595-603.   DOI