The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-kappaB activation in oesophageal cells, with a mechanism of action involving ROS.
Deoxycholic acid (DCA) is a secondary bile acid implicated in various cancers of the gastrointestinal (GI) tract. In oesophageal adenocarcinoma, DCA is believed to contribute to carcinogenesis during reflux where stomach contents enter the lower oesophagus. It is imperative that we understand the mechanisms whereby oesophageal carcinogens function in order that therapeutic options may be developed. We have previously shown that DCA can damage chromosomes and does so through its generation of reactive oxygen species (ROS). We show here, after detailed experiments, that DCA appears to have a non-linear dose response for DNA damage. DCA induces DNA damage (as measured by the micronucleus assay) at doses of 100 microM and higher in oesophageal OE33 cells, but fails to induce such DNA damage below this cut-off dose. We also show that in terms of NF-kappaB activation (as measured by up-regulation of two NF-kappaB target genes) by DCA, a similar dose response is observed. This dose-response data may be important clinically as DCA exposure to the oesophagus may be used as a way to identify the 10% of Barrett's oesophagus patients currently progressing to cancer from the 90% of patients who do not progress. Only quantitative studies measuring DCA concentrations in refluxates correlated with histological progression will answer this question. We further show here that ROS are behind DCAs ability to activate NF-kappaB as antioxidants (epigallocatechin gallate, resveratrol and vitamin C) abrogate DCAs ability to up-regulate NF-kappaB-controlled genes. In conclusion, low doses of DCA appear to be less biologically significant in vitro. If this were to be confirmed in vivo, it might suggest that reflux patients with low DCA concentrations may be at a lower risk of cancer progression compared to patients with high levels of DCA in their refluxate. Either way, antioxidant supplementation may possibly help prevent the deleterious effects of DCA in the whole GI tract.
Institute of Life Science, Swansea School of Medicine, Swansea University, Swansea SA2 8PP, UK. g.j.jenkins@swansea.ac.uk
G J S
GJ
Jenkins
J
J
Cronin
A
A
Alhamdani
N
N
Rawat
F
F
D'Souza
T
T
Thomas
Z
Z
Eltahir
A P
AP
Griffiths
J N
JN
Baxter
D000230:Adenocarcinoma / Q000139:chemically induced / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D001471:Barrett Esophagus / Q000150:complications; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D003840:Deoxycholic Acid / Q000633:toxicity*; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D004947:Esophagus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D015162:Micronucleus Tests; D009153:Mutagens / Q000633:toxicity*; D016328:NF-kappa B / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
D009153:Mutagens; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D003840:Deoxycholic Acid; D004247:DNA