Research on developmental mechanisms of drug-induced gingival overgrowth: experiments in animal and cellular levels

1.人牙龈成纤维细胞实验：1）当检测钙通道阻断剂硝苯地平对人牙龈成纤维细胞（HGF）增殖和凋亡的影响时，发现硝苯地平以剂量依赖的方式抑制HGF增殖和凋亡。2）硝苯地平抑制脂多糖（LPS）诱导的巨噬细胞样细胞（RAW 264）产生一氧化氮（NO）和凋亡。3）LPS刺激可诱导与RAW 264共同培养的HGF细胞凋亡，但LPS刺激后，细胞凋亡率明显降低，4）苯妥英钠能促进基质金属蛋白酶（MMPs）mRNA的表达这些结果提示硝苯地平或苯妥英钠对HGF增殖、凋亡和炎症反应的影响与药物诱导的牙龈增生密切相关。大鼠牙龈过度生长中的药物相互作用1）为了阐明药物相互作用对牙龈过度生长的影响，用硝苯地平和/或影响硝苯地平代谢的酮康唑处理大鼠。与仅用硝苯地平治疗的大鼠相比，酮康唑治疗诱导了更高的硝苯地平血药浓度和更严重的牙龈过度生长2）当大鼠用硝苯地平治疗并同时给予葡萄柚汁或佛手柑油时，在给予

1. Human Gingival Fibroblast Experiments: in vitro1) When effects ofnifedipine, a calcium channel btocfcer, on cell proliferation and apoptosis were examined in human gingival fibroblast (HGF) cultures, both of these were suppressed by the drug in a dose dependent manner2) Nifedipine inhibited lipopolysaccharide (LPS)induced nitric oxide (NO) production and apoptosis of macrophage like cells (RAW264). Furthermore, LPSinduced NO synthetase (iNOS) production was also inhibited by adding nifedipine to the RAW 264 ceil cultures3) LPS stimulation induced the apoptosis ofHGF cultured with RAW264, however, this apoptosis was suppressed by the addition of nifedipine to the culture4) Phenytoin enhanced the mRNA production of matrix metaloproreases (MMPs) and their inhibitors in the HGF culturesThese findings are suggesting that the close relationship exists between the effects ofnifedipine or phenytoin on the proliferation, apoptosis and inflammatory reaction of HGF and the druginduced gingival overgrowth2. Drug Interaction in Gingival Overgrowth in Rats1) To elucidate the effects of drug interaction on gingival overgrowth, rats were treated with nifedipine and/or ketoconazole which affects the nifedipine metabolism. Ketoconazole treatment induced higher blood nifedipine level and more severe gingival overgrowth in rats than those treated with nifedipine only2) When rats were treated with nifedipine and administered grapefruitjuice or bergamot oil concomitantly, an increase in severity of nifedipineinduced gingival overgrowth was found in rats given