Jeng J H, Ho Y S, Chan C P, Wang Y J, Hahn L J, Lei D, Hsu C C, Chang M C
Laboratory of Dental Pharmacology and Toxicology, Graduate Institute of Clinical Dental Science, National Taiwan University, Taipei.
Carcinogenesis. 2000 Jul;21(7):1365-70.
There are about 600 million betel quid (BQ) chewers in the world. BQ chewing is associated with increased incidence of oral cancer and submucous fibrosis. In this study, areca nut (AN) extract (200-800 microg/ml) induced the prostaglandin E(2) (PGE(2)) production by 1. 4-3.4-fold and 6-keto-PGF(1 alpha) production by 1.1-1.7-fold of gingival keratinocytes (GK), respectively, following 24 h of exposure. Exposure of GK to AN extract (>400 microg/ml) led to cell retraction and intracellular vacuoles formation. At concentrations of 800 and 1200 microg/ml, AN extract induced cell death at 21-24 and 32-52% as detected by MTT assay and cellular lactate dehydrogenase release, respectively. Interestingly, AN-induced morphological changes of GK are reversible. GK can still proliferate following exposure to AN extract. Cytotoxicity of AN extract cannot be inhibited by indomethacin (1 microM) and aspirin (50 microM), indicating that prostaglandin (PG) production is not the major factor responsible for AN cytotoxicity. PGE(2) exhibited little effect on the growth of GK at concentrations ranging from 100-1000 pg/ml. Stimulating GK production of PGs by AN extract could be due to induction of cyclooxygenase-2 (COX-2) mRNA expression and protein production. These results suggest that AN ingredients are critical in the pathogenesis of oral submucous fibrosis and oral cancer via their stimulatory effects on the PGs, COX-2 production and associated tissue inflammatory responses. AN cytotoxicity to GK is not directly mediated by COX-2 stimulation and PG production.
全球约有6亿槟榔咀嚼者。咀嚼槟榔与口腔癌和口腔黏膜下纤维化发病率增加有关。在本研究中，槟榔提取物（200 - 800微克/毫升）作用24小时后，可使牙龈角质形成细胞（GK）的前列腺素E2（PGE2）生成增加1.4 - 3.4倍，6 - 酮 - 前列腺素F1α（6 - keto - PGF1α）生成增加1.1 - 1.7倍。将GK暴露于槟榔提取物（>400微克/毫升）会导致细胞收缩和细胞内空泡形成。通过MTT法和细胞乳酸脱氢酶释放检测发现，在800和1200微克/毫升浓度下，槟榔提取物分别在21 - 24%和32 - 52%时诱导细胞死亡。有趣的是，槟榔诱导的GK形态变化是可逆的。GK在暴露于槟榔提取物后仍能增殖。吲哚美辛（1微摩尔）和阿司匹林（50微摩尔）不能抑制槟榔提取物的细胞毒性，这表明前列腺素（PG）生成不是槟榔细胞毒性的主要因素。在100 - 1000皮克/毫升浓度范围内，PGE2对GK生长几乎没有影响。槟榔提取物刺激GK生成PGs可能是由于诱导了环氧化酶 - 2（COX - 2）mRNA表达和蛋白质生成。这些结果表明，槟榔成分通过对PGs、COX - 2生成及相关组织炎症反应的刺激作用，在口腔黏膜下纤维化和口腔癌的发病机制中起关键作用。槟榔对GK的细胞毒性不是由COX - 2刺激和PG生成直接介导的。
