Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: the potential role of anti-oxidants in Barrett's oesophagus
Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: the potential role of anti-oxidants in Barrett's oesophagus
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DOI：
10.1093/carcin/bgl147
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发表时间：
2007-01-01
期刊：
影响因子：
4.7
通讯作者：
Baxter, John N.
中科院分区：
文献类型：
--
作者：
Jenkins, Gareth J. S.;D'Souza, Francis R.;Baxter, John N.
胆汁酸通常回流到食管下部，是食管腺癌发展的候选致癌物。我们在这里表明，二级胆汁酸，脱氧胆酸（DCA），是唯一一种常见的回流胆汁酸在这里测试，显示遗传毒性，在人类p53基因的染色体损伤和突变诱导。这种遗传毒性在中性和酸性pH值下都很明显，而在酸性pH值下胆汁诱导的毒性显著增加。酸性pH值下细胞死亡水平较高和细胞存活率较低可能意味着酸性胆汁暴露是有毒的，而不是致癌的，因为死细胞不会引发癌症。我们还表明，DCA（在中性和酸性pH值）诱导暴露细胞的细胞质内的活性氧（ROS）的释放。我们进一步证明了DCA的遗传毒性是ROS介导的，因为当细胞用DCA+抗氧化剂维生素C处理时，微核诱导显著降低。总之，我们表明，DCA，是一种有效的遗传毒素在中性和酸性pH值。由于胆汁酸如DCA可以诱导DNA损伤在中性pH值，抑制酸性的回流液不会完全消除其致癌潜力。然而，DCA的遗传毒性是ROS依赖性的，因此除了酸抑制之外，抗氧化剂补充剂可以阻断DCA驱动的Barrett患者的致癌作用。
Bile acids are often refluxed into the lower oesophagus and are candidate carcinogens in the development of oesophageal adenocarcinoma. We show here that the secondary bile acid, deoxycholic acid (DCA), is the only one of the commonly refluxed bile acids tested here, to show genotoxicity, in terms of chromosome damage and mutation induction in the human p53 gene. This genotoxicity was apparent at both neutral and acidic pH, whilst there was a considerable increase in bile-induced toxicity at acidic pH. The higher levels of cell death and low cell survival rates at acidic pH may imply that acid bile exposure is toxic rather than carcinogenic, as dead cells do not seed cancer development. We also show that DCA (at neutral and acid pH) induced the release of reactive oxygen species (ROS) within the cytoplasm of exposed cells. We further demonstrate that the genotoxicity of DCA is ROS mediated, as micronucleus induction was significantly reduced when cells were treated with DCA + the anti-oxidant vitamin C. In conclusion, we show that DCA, is an effective genotoxin at both neutral and acidic pH. As bile acids like DCA can induce DNA damage at neutral pH, suppressing the acidity of the refluxate will not completely remove its carcinogenic potential. The genotoxicity of DCA is however, ROS dependent, hence anti-oxidant supplementation, in addition to acid suppression may block DCA driven carcinogenesis in Barrett's patients.