title: Fibrotic Effects of Arecoline N-Oxide in Oral Potentially Malignant Disorders.
abstract: The metabolites of environmental chemicals play key roles in carcinogenesis. Areca nut is strongly associated with the development of oral potentially malignant disorders (OPMD) or cancer. The main alkaloid in the areca nut is arecoline, which is highly cytotoxic and genotoxic. Arecoline N-oxide, a metabolite of areca nut alkaloids, which has been identified in animal urine, has been shown to induce mutagenicity in bacteria. In this study, it was found that its protein adduct could be detected in oral keratinocytes treated with areca nut extract. Increased collagen expression and severity of squamous hyperplasia were observed in arecoline N-oxide treated mice. In cultured oral fibroblasts, arecoline N-oxide showed stronger effects on the increase of fibrotic related genes including TGF-beta1, S100A4, MMP-9, IL-6, and fibronectin and a decrease of E-cadherin as compared with arecoline. Finally, arecoline N-oxide stimulation effectively increased the DNA damage marker, gamma-H2A.X, both in vitro and in vivo. Taken together, these results indicate that arecoline N-oxide shows a high potential for the induction of OPMD.
authors.affiliation: †Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan.|ΘGraduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Tzer-Min
authors.initials: TM
authors.lastname: Kuo
authors.affiliation: ‡Department of Chemistry, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Shun-Yuan
authors.initials: SY
authors.lastname: Luo
authors.affiliation: †Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan.|§Department of Health Risk Management, College of Management, China Medical University, Taichung, Taiwan.
authors.forename: Shang-Lun
authors.initials: SL
authors.lastname: Chiang
authors.affiliation: ΔDepartment of Pathology, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Kun-Tu
authors.initials: KT
authors.lastname: Yeh
authors.affiliation: ΔDepartment of Pathology, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Hui-Ting
authors.initials: HT
authors.lastname: Hsu
authors.affiliation: ⊥Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Tien
authors.initials: CT
authors.lastname: Wu
authors.affiliation: #Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: Lu
authors.affiliation: ΠDepartment of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Ming-Hsui
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: ⊗Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan.|ΘGraduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Jan-Gowth
authors.initials: JG
authors.lastname: Chang
authors.affiliation: †Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan.|ΘGraduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Ying-Chin
authors.initials: YC
authors.lastname: Ko
mesh_terms: D000818:Animals; D001114:Areca / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D001115:Arecoline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000009:adverse effects* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D005638:Fruit / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009059:Mouth Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism
chemical_list: D003497:Cyclic N-Oxides; D015850:Interleukin-6; C518971:arecoline 1-oxide; D001115:Arecoline; D020780:Matrix Metalloproteinase 9
keywords: areca nut; arecoline; arecoline N-oxide; collagen; fibrosis