Modification of N-methyl-N'-nitro-N-nitrosoguanidine-induced forestomach and glandular stomach carcinogenesis by phenolic antioxidants in rats.

The modifying effects of five phenolic antioxidants on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-initiated forestomach and glandular stomach carcinogenesis were investigated in male F344 rats. Groups of 20 rats were given an intragastric dose of 150 mg/kg body weight MNNG, and starting from 1 week later received diet supplemented with 0.8% catechol (CC), 1.0% 2-tert-butyl-4-methylphenol, 1.5% p-tert-butyl-phenol, 1.5% methylhydroquinone, 1.5% 4-methoxyphenol (4MP), or basal diet alone for 51 weeks. Further groups of 10-15 rats were maintained as controls without prior treatment with MNNG. The incidences of squamous cell carcinoma of the forestomach in MNNG-treated animals were significantly elevated by the diets containing CC (P less than 0.001), 2-tert-butyl-4-methylphenol (P less than 0.001), or p-tert-butylphenol (P less than 0.01), while the development of carcinoma in situ was inhibited by 4MP (P less than 0.01). Treatment with CC, 2-tert-butyl-4-methylphenol, p-tert-butylphenol, or 4MP alone induced forestomach hyperplasia at incidences of 86.7, 40, 93.3, and 100%, respectively. In the pyloric region of the glandular stomach, the development of adenomatous hyperplasia and adenocarcinoma after MNNG treatment was significantly enhanced by diet containing CC (P less than 0.001). Moreover, treatment with CC alone induced 100% adenomatous hyperplasia and induced adenocarcinoma in 20% of animals. These results clearly demonstrated that while antioxidants causing proliferation in forestomach epithelium can markedly enhance carcinogenesis in this tissue, others displaying the same or greater potential for generating a hyperplastic response, like 4MP, can exert an inhibitory effect. In addition, it was shown that CC, which is widely present in our environment, is an unequivocal glandular stomach carcinogen also possessing strong enhancing activity for MNNG-induced lesion development.