Esophageal carcinogen

A toxic component of braken fern, perhaps either quercetin (105) or ptaquiloside, a glucoside (106), has a mixed history of carcinogenicity. It is sometimes impHcated in an increased incidence of bladder cancer in animals and esophageal cancer in humans. Multiple other dietary components seem to either promote or interfere with its action, and the significance of braken fern in human carcinogenesis remains unproven. 

NNN is formally a derivative of NPYR, but the pyridine ring has a marked effect on its metabolism and carcinogenicity. NNN induces lung adenomas in mice, esophageal and nasal cavity tumors... 

NPIP induces esophageal and nasal cavity tumors in the rat, forestomach, liver and lung tumors in the mouse, and tracheal tumors in the Syrian golden hamster (43, 44, 45). Its potent carcinogenicity is indicated by the fact that a single dose of only 22 mg/kg was sufficient to induce tumors in 20% of Syrian golden hamsters (45). The environmental occurrence of NPIP appears to be less frequent than that of NPYR, but it has been detected in food (J, 44). 

The related unsaturated compounds, N-nitroso-1,2,3,6-tetra-hydropyridine and N-nitroso-1,2,3,4-tetrahydropyridine, have been tested for carcinogenicity and both were potent esophageal carcinogens, as is nitrosopiperidine. However, N-nitroso-1,2,3,6-tetrahydropyridine also produced liver tumors, whereas N-nitro-so-1,2,3,4-tetrahydropyridine also gave tumors of the forestomach and oropharynx. The difference in tumor spectrum between the two unsaturated isomers may be related to differences in metabolism. N-Nitroso-1,2,3,6-tetrahydropyridine isomerized to N-nitro-so-1,2,3,4-tetrahydropyridine in vivo, but the reverse reaction was not observed (49). 

Both l-nitroso-3,5-dimethylpiperazine and l-nitroso-3,4,5-trimethylpiperazine induced a high incidence of thymic leukemia in rats within 6 months (23). The 4-acetyl derivative of the former induced esophageal tumors in the same time, while the 4-benzoyl derivative was a very much weaker carcinogen, giving rise to only a few tumors of the forestomach after almost 2 years. These contrasting results are difficult to reconcile with any simple mechanism of carcinogenesis. 

In rats, esophagogastroduodenal anastomosis, which 96 induces reflux of gastric acid and bile, without concomitant chemical carcinogen treatment, can lead to esophageal adenocarcinoma. 

In rats, esophagojejunostomy with total gastrectomy 97 to induce reflux of duodenal juice alone resulted in BE and esophageal adenocarcinoma in 16 weeks without any carcinogen. 

One of the more important classes of chemical carcinogens are N-nitrosamines. They are important because practically all of the simple nitrosamines are carcinogenic, they are widely distributed in our environment and can be formed in the stomach from secondary and tertiary amines and the ubiquitous nitrite ion. Moreover, nitrosamines are very organ-specific. Thus, a given nitrosamine will produce a liver or an esophageal tumor, regardless of the route of administration of the carcinogen. This fact makes nitrosamines very useful in the study of mechanisms of tumor induction (1). 

NNN induces esophageal and nasal cavity tumors in rats,tracheal timiors in hamsters, and lung adenomas in strain A mice. NNK is more tumorigenic than NNN in strain A mice and NNA is inactive in this species. NAB is less carcinogenic than NNN in both rats... 

The most direct way of testing the possibility that reaction of an ingested amine with nitrite can give rise to sufficient of a carcinogenic N-nitroso compound to induce tumors has been to feed the amine and nitrite simultaneously to animals for most of their lifespan. The first successful experiment of this type was that of Sander and BUrkle ( ), using the amine methyl benzyl amine, which when fed to rats with nitrite induced esophageal tumors, the same tumor induced in rats by feeding nitrosomethyl benzyl amine. Similar experiments were carried out in mice with piperazine (24), and in rats with heptamethyleneimine (25). 

We have fed control and zinc-deficient rats their respective diets and administered N-nitrosodimethylamine (DMN) at a dose level of 2 mg/kg twice weekly for 3 weeks followed by 4 mg/kg of the same carcinogen for another 5 weeks, a total of 52 mg/kg. After 45 weeks none of the control rats had developed esophageal or forestomach lesions but, as shown in Table VIII, most of the zinc-deficient rats developed forestomach lesions or tumors (28). Mechanisms for this interesting observation are unclear but the underlying toxicology probably resides in metabolism affecting the site of tumor occurrence and type of activation of DMN. 

Dr. Henry Foy (personal communication) has drawn attention to the severe effects of riboflavin deficiency in the baboon, with particular attention to the dysplasia of the epithelium of the oral cavity and esophagus. Dr. Foy has pursued these studies for many years at the Wellcome Research Laboratories in Nairobi. We have observed similar lesions in the Rhesus monkey, and have further pursued the effects of riboflavin deficiency in the rat. We have superimposed an esophageal carcinogen (MBN) on the deprived, damaged oral cavity and esophageal epithelium. Table IX lists results of a five month study, emphasizing the profound enhancement the deficiency can have on the esophagus (31). 

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