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Protective Effect of Caffeic Acid Derivatives on tert-Butyl Hydroperoxide-Induced Oxidative Hepato-Toxicity and Mitochondrial Dysfunction in HepG2 Cells

Department of Dentistry, Keelung Chang-Gung Memorial Hospital, Keelung 204, Taiwan
Department of Pediatrics, Taipei Tzu-Chi Hospital, Buddhist Tzu-Chi Medical Foundation, New Taipei City 231, Taiwan
Department of Pediatrics, College of Medicine, Buddhist Tzu-Chi University, Hualien 970, Taiwan
Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan
Institute of Microbiology and Biochemistry, and Department of Biochemical Science and Technology, National Taiwan University, Taipei 106, Taiwan
Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 404, Taiwan
Department of Biotechnology, Asia University, Taichung 413, Taiwan
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Diego Muñoz-Torrero
Molecules 2017, 22(5), 702;
Received: 20 February 2017 / Revised: 19 April 2017 / Accepted: 25 April 2017 / Published: 28 April 2017
(This article belongs to the Section Medicinal Chemistry)
Oxidative stress results in structural and functional abnormalities in the liver and is thought to be a crucial factor in liver diseases. The aim of this study was to investigate the cytoprotective and antioxidant effects of caffeic acid (CA) derivatives on tert-butyl hydroperoxide (t-BHP)-induced oxidative stress in HepG2 cells. Nine CA derivatives were synthesized, including N-phenylethyl caffeamide (PECA), N-(3-florophen)methyl caffeamide (FMCA), N-(4-methoxy-phen)methyl caffeamide (MPMCA), N-heptyl caffeamide (HCA), N-octyl caffeamide (OCA), octyl caffeate (CAOE), phenpropyl caffeate (CAPPE), phenethyl caffeate (CAPE), and phenmethyl caffeate (CAPME). The results showed that CA and its derivatives significantly inhibited t-BHP-induced cell death of HepG2 cells. The rank order of potency of the CA derivatives for cytoprotection was CAOE > HCA > OCA > FMCA > CAPPE > CAPME > CAPE > PECA > MPMCA > CA. Their cytoprotective activity was associated with lipophilicity. The antioxidant effect of these compounds was supported by the reduction in the levels of thiobarbituric acid reactive substrates, a biomarker of lipid peroxidation, in HepG2 cells. Pre-treatment of CA derivatives significantly prevented the depletion of glutathione, the most important water-soluble antioxidant in hepatocytes. Pre-treatment of CA derivatives before t-BHP exposure maintained mitochondrial oxygen consumption rate and ATP content in the injured HepG2 cells. CA derivatives except OCA and HCA significantly suppressed t-BHP-induced hypoxia-inducible factor-1α (HIF-1α) protein level. In addition, all of these CA derivatives markedly increased the nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation in the nucleus, indicating that their cytoprotection may be mediated by the activation of Nrf2. Our results suggest that CA derivatives might be a hepatoprotective agent against oxidative stress. View Full-Text
Keywords: caffeic acid derivatives; tert-butyl hydroperoxide; antioxidant; liver protection caffeic acid derivatives; tert-butyl hydroperoxide; antioxidant; liver protection
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Tsai, T.-H.; Yu, C.-H.; Chang, Y.-P.; Lin, Y.-T.; Huang, C.-J.; Kuo, Y.-H.; Tsai, P.-J. Protective Effect of Caffeic Acid Derivatives on tert-Butyl Hydroperoxide-Induced Oxidative Hepato-Toxicity and Mitochondrial Dysfunction in HepG2 Cells. Molecules 2017, 22, 702.

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