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ToxSci Advance Access originally published online on August 6, 2007
Toxicological Sciences 2007 100(1):66-74; doi:10.1093/toxsci/kfm201
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Characterization of Arecoline-Induced Effects on Cytotoxicity in Normal Human Gingival Fibroblasts by Global Gene Expression Profiling

Shang-Lun Chiang*, Shih-Sheng Jiang{dagger}, Yi-Jou Wang{ddagger}, Horn-Che Chiang§, Ping-Ho Chen|||, Hung-Pin Tu§, Kun-Yen Ho,||, Yu-Shan Tsai|||, I-Shou Chang{dagger} and Ying-Chin Ko*,|||,1

* Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan, ROC {dagger} National Institute of Cancer Research, National Health Research Institutes, Taiwan, ROC {ddagger} Graduate Institute of Oral Health Sciences, College of Dental Medicine, Kaohsiung Medical University, Taiwan, ROC § Department of Public Health, College of Medicine, Kaohsiung Medical University, Taiwan, ROC College of Dental Medicine, Kaohsiung Medical University, Taiwan, ROC || Division of Periodontics, Department of Dentistry, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Taiwan, ROC ||| Division of Environmental Health and Occupational Medicine, National Health Research Institutes, 100, Shi-chuan 1st Road, Kaohsiung 807, Taiwan, ROC

1 To whom correspondence should be addressed. Fax: +886-7-316-2725. E-mail: ycko{at}nhri.org.tw.

Received May 9, 2007; accepted July 23, 2007


  Abstract

Areca nut is the most widely used psychoactive substance and an important environmental risk factor for development of oral premalignant lesions and cancer. Arecoline, the major alkaloid of areca nut, has been known to cause cytotoxicity and genotoxicity in mammalian cells in vivo and in vitro and even contributes to carcinogenicity. However, the susceptible genes accounting for arecoline-induced damage in normal human oral cells are still lacking, which possibly involves in initial molecular damage via alternation of gene expression level on biological pathways. The present study was undertaken to characterize the toxic effects of arecoline in gene expression profiling on normal human gingival fibroblasts (HGF) using cDNA microarray and quantitative real-time reverse transcription PCR. The cytotoxicity of arecoline on HGF-1 cell line was elevated in a dose-dependent manner (p < 0.05) accompanied with distinct morphological change and formation of intracellular vacuoles were observed. At optimum concentration of arecoline determined from dose-response curve of the cytotoxicity, a large number of genes were significantly repressed than induced by arecoline in global gene expression profiling. Five induced- and seven repressed genes including glutathione synthetase were further validated, and their gene expression changes were increased in a dose-dependent manner in a concentration range of 50–150 µg/ml. In conclusion, we proposed a tentative model to explain arecoline-induced effects on contribution of oral pathogenesis. The findings identified that 12 susceptible genes can potentially serve as biomarkers of arecoline-induced damage in betel chewers.

Key Words: arecoline; cytotoxicity; gene expression; human gingival fibroblasts; betel chewing.


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