Duodenogastric reflux and foregut carcinogenesis: analysis of duodenal juice in a rodent model of cancer.
The incidence of esophageal adenocarcinoma is increasing rapidly. In rats, surgically induced duodenoesophageal reflux is carcinogenic. One proposed mechanism of carcinogenesis is based on the reaction of physiological bile acids with nitrite to produce carcinogenic N:-nitroso amides. To test this hypothesis, duodenal juice was analyzed for endogenously formed N:-nitroso bile acids and its genotoxicity was determined. Esophagojejunostomy was performed on 15 Sprague-Dawley rats to produce duodeno-esophageal reflux. At the time of surgery and 2 and 6 weeks later, duodenal contents were aspirated and analyzed immediately. High performance liquid chromatography coupled to tandem mass spectrometry was used to detect bile acids and their nitroso derivates. Genotoxicity was assessed using a micronucleus test. The characteristic pattern of bile acid derivatives, with taurocholic acid (TCA) and glycocholic acid (GCA) as the predominant conjugates, was detected in all samples. However, even selective reaction monitoring experiments failed to demonstrate the presence of any N:-nitroso-TCA or N:-nitroso-GCA. In addition, other nitroso derivatives could not be detected in any of the samples by neutral loss experiments monitoring the loss of nitric oxide (detection limit 0.1% of the concentration of TCA). All samples were cytotoxic, but neither the preoperative nor the postoperative samples were genotoxic. Duodenal juice was cytotoxic but not genotoxic. Tumorigenesis of esophageal adenocarcinoma in the rodent model could not be linked to a specific carcinogen, especially not to nitroso bile acids. Chronic inflammation is likely to be the mechanism of carcinogenesis by duodenogastric reflux.
Fein
M
M
Department of Surgery, Institute for Toxicology and Institute of Pharmacy and Food Chemistry, University of Würzburg, Germany. fein@chirurgie.uni-wuerzburg.de
Fuchs
K H
KH
Stopper
H
H
Diem
S
S
Herderich
M
M
D000230:Adenocarcinoma / Q000209:etiology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004383:Duodenogastric Reflux / Q000150:complications*; D004386:Duodenum / Q000378:metabolism; D004848:Epithelium / Q000473:pathology; D004938:Esophageal Neoplasms / Q000209:etiology*; D004942:Esophagitis, Peptic / Q000209:etiology / Q000473:pathology; D004947:Esophagus / Q000601:surgery; D005743:Gastrectomy; D007419:Intestinal Secretions / Q000737:chemistry*; D007583:Jejunum / Q000601:surgery; D013058:Mass Spectrometry; D015162:Micronucleus Tests; D009602:Nitrosamines / Q000032:analysis* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D009602:Nitrosamines; C034937:N-nitrosoglycocholic acid; C034936:N-nitrosotaurocholic acid