Reactive oxygen species are crucial for hydroxychavicol toxicity toward KB epithelial cells |
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Authors: | J. H. Jeng Y. J. Wang W. H. Chang H. L. Wu C. H. Li B. J. Uang J. J. Kang J. J. Lee L. J. Hahn B. R. Lin M. C. Chang |
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Affiliation: | (1) Department of Dentistry, College of Medicine, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan;(2) Department of Environmental Medicine and Occupational Health, National Cheng-Kung University, Tainan, Taiwan;(3) Department of Applied Chemistry, Chung-Shan Medical University, Taichung, Taiwan;(4) Department of Chemistry, National Tsing-Hua University, Hsin-Chu, Taiwan;(5) Graduate Institute of Toxicology, National Taiwan University, Taipei, Taiwan;(6) Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, No 1, Chang-Te Street, Taipei, Taiwan;(7) Biomedical Science Team, Chang-Gung Institute of Technology, 261, Wen-Hwa 1 Road, 33333 Taoyuan, Taiwan |
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Abstract: | Betel quid (BQ) chewing shows a strong correlation to the incidence of oral submucous fibrosis (OSF), leukoplakia and oral cancer. BQ contains mainly areca nut, lime, Piper betle leaf (PBL) and the inflorescence of P. betle (IPB). Hydroxychavicol (4-allyl-catechol, HC), as a major phenolic compound in PBL and IPB, is shown to induce oxidative stress, glutathione (GSH) depletion and cell cycle deregulation. Using bivariate BrdU/PI flow cytometry, KB cells in DNA synthesis (S phase) are shown to be sensitive to the toxic effect of HC and show cell cycle arrest and apoptosis following exposure to 0.1 and 0.3 mM HC. HC-induced apoptosis and cell cycle arrest are associated with mitochondrial membrane potential (![Delta](/content/pnq5474yenltmjq2/xxlarge916.gif) m) depolarization as revealed by a decrease in rhodamine fluorescence. N-acetyl-L-cysteine (1 mM), superoxide dismutase (100 U/ml) and catalase (1000 U/ml) were effective in prevention of HC-induced GSH depletion (as indicated by chloromethylfluorescein fluorescence), reactive oxygen species (ROS) production (by dichlorofluorescein fluorescence), cell cycle arrest and apoptosis. However, dimethylthiourea (2 mM), neocuproine (1 mM), 1,10-phenanthroline (200 M) and desferrioxamine (0.5 mM) showed little effect on HC-induced cell changes. HC elevated the cellular and mitochondrial GSH levels at moderate concentrations (0.05–0.1 mM), whereas at a concentration of 0.3 mM, inhibitory effects were noted. These results indicate that HC consumption may be associated with BQ-chewing-related oral mucosal diseases via GSH depletion, ROS production, mitochondrial dysfunction, cell cycle disturbance and the induction of apoptosis. These events are related to the production of superoxide radicals and hydrogen peroxide.Received 9 July 2003; received after revision 28 September 2003; accepted 24 October 2003 |
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Keywords: | Apoptosis betel quid cell cycle glutathione hydroxychavicol mitochondrial membrane potential reactive oxygen species |
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