Metabolism of Carcinogenic Nitrosamines in the Rat and Human Esophagus and Induction of Esophageal Adenocarcinoma in Rats

S. S. Mirvish; Q. Huang; S. C. Chen; D. F. Birt; G. W. B. Clark; R. A. Hinder; T. C. Smyrk; T. R. DeMeester

doi:10.1055/s-2007-1010418

Endoscopy 1993; 25(9): 627-631
DOI: 10.1055/s-2007-1010418

Metabolism of Carcinogenic Nitrosamines in the Rat and Human Esophagus and Induction of Esophageal Adenocarcinoma in Rats

S. S. Mirvish^{1, 2, 3} , Q. Huang¹ , S. C. Chen¹ , D. F. Birt^{1, 2} , G. W. B. Clark⁴ , R. A. Hinder⁵ , T. C. Smyrk⁶ , T. R. DeMeester⁴

¹Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska
²Department of Biochemistry, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
³Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska
⁴Department of Surgery, University of Southern California Medical Center, Los Angeles, California
⁵Department of Surgery, Creighton University Medical School, Omaha, Nebraska
⁶Department of Pathology, Clarkson Hospital, Omaha, Nebraska, USA

Abstract

PDF Download

Abstract

The mechanism is discussed by which certain nitrosamines induce esophageal papillomas and squamous cancer in rats, and some evidence is presented for the view that nitrosamines also induce the same cancer in humans, especially in China and South Africa. Studies on the metabolism of nitrosamines by cytochrome P450 isozymes in rat and human esophagus, including the activation reactions of formaldehyde and pentaldehyde formation from methyl-n-amylnitrosamine (MNAN), are reviewed. These reactions are catalyzed by microsomes from the rat and human esophagus, probably because these microsomes contain specific cytochrome P450 isozymes. Evidence is reviewed for the occurrence of nitrosamines related to MNAN in Fungus-infected corn. The incidence of esophageal adenocarcinoma is rising in Western countries. The precursor lesion, Barrett's esophagus, is associated with colon cancer, suggesting a role for bile salts in the induction of the esophageal tumor. Studies are described in which rats were subjected to esophago-duodenostomy (joining the duodenum to the esophagus) and then treated with nitrosamines that normally induce esophageal squamous cancer. Adenocarcinomas of the lower esophagus were induced as well as Barrett's esophagus (under one set of conditions). Feeding a high-fat diet with this system increased the incidence of esophageal adenocarcinoma. This tumor was not induced when the operation was changed to esophago-gastroplasty (widening the lower esophageal sphincter). These results support a role of reflux of duodenal contents (including bile and pancreatic juice) rather than of gastric contents in the etiology of human esophageal adenocarcinoma.

PDF (528 kb)