Biomarkers associated with binaprofen‑induced liver injury

Guo,Qiuping; Guo,Jianmin; Chen,Guiying; Han,Zhong; Xiao,Baiquan; Jin,Ruomin; Liang,Chun; Yang,Wei

doi:10.3892/mmr.2018.9549

Biomarkers associated with binaprofen‑induced liver injury

Authors:
- Qiuping Guo
- Jianmin Guo
- Guiying Chen
- Zhong Han
- Baiquan Xiao
- Ruomin Jin
- Chun Liang
- Wei Yang
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Affiliations: Drug Non‑Clinical Evaluation and Research Center of Guangzhou General Pharmaceutical Research Institute, Guangzhou, Guangdong 510240, P.R. China, Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Guangdong Institute of Applied Biological Resources, Guangzhou, Guangdong 510990, P.R. China, Drug Safety Evaluation Center of Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China, Division of Life Science, Center for Cancer Research, State Key Lab for Molecular Neural Science, Bioengineering Graduate Program, Hong Kong University of Science and Technology, Hong Kong, SAR 999077, P.R. China
Published online on: October 10, 2018 https://doi.org/10.3892/mmr.2018.9549
Pages: 5076-5086

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Abstract

Drug‑induced liver injury (DILI) is a common hepatic disease. The identification of biomarkers for DILI prediction is critical for rational drug use. The aim of the present study was to investigate liver injury caused by binaprofen and identify proteins that may serve as early biomarkers to predict DILI. For in vivo DILI assays, zebrafish were exposed to acetaminophen (APAP) and binaprofen for 12‑96 h before lethal concentration 50 (LC50), histopathological analysis, conventional and non‑conventional biomarker measurements were conducted. In vitro assays were performed in cultured liver cells; after 6‑24 h treatment with APAP and binaprofen the same measurements were conducted as aforementioned. The in vivo assays indicated that the LC50 of APAP was 5.2 mM, whereas the LC50 of binaprofen was 1.2 mM; 12‑48 h post‑treatment, liver cells exhibited mild to moderate vacuolization in a time‑ and concentration‑dependent manner in response to both drugs. During this time, conventional and non‑conventional biomarkers were also altered in a time‑ and concentration‑dependent manner; however, alterations in the levels of non‑conventional biomarkers occurred at an earlier time point compared with conventional biomarkers. The in vitro assays indicated that the half maximal inhibitory concentration (IC50) of APAP was 16.2 mM, whereas the IC50 of binaprofen was 5.3 mM; 12‑48 h post‑treatment, cultured liver cells exhibited mild to moderate swelling in a time‑ and concentration‑dependent manner. Alterations in the levels of conventional and non‑conventional biomarkers were similar to those observed in the in vivo assays. As a non‑steroidal anti‑inflammatory drug, binaprofen exhibited expected levels of liver toxicity in in vitro and in vivo assays, which were similar to APAP. Total bile acid and argininosuccinate lyase were identified as early biomarkers, which could accurately predict onset of binaprofen‑induced liver injury.

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