Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.108
Ibuprofen Increases the Hepatotoxicity of Ethanol through Potentiating Oxidative Stress
Minjeong Kim1, Eugenia Jin Lee2 and Kyung-Min Lim1,*
1College of Pharmacy, Ewha Womans University, Seoul 37060, Republic of Korea
2Department of Biological Sciences, Columbia College, Columbia University, NY 10027, USA
*E-mail: kmlim@ewha.ac.kr
Tel: +82-2-3277-3055, Fax: +82-2-3277-3760
Received: June 15, 2020; Revised: August 22, 2020; Accepted: August 25, 2020; Published online: October 7, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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


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