methylnitronitrosoguanidine and catechol

Combined effects of catechol, sodium chloride (NaCl) and ethanol on the post-initiation stage of gastric carcinogenesis were examined in rats pretreated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). F344 male rats were given a single intragastric dose of 150 mg/kg b.w. MNNG at 6 weeks of age. Starting 1 week thereafter, groups of 15 rats were administered 0.8% catechol, 5% NaCl and 10% ethanol either individually or in combination, or basal diet alone for 51 weeks. Further groups of animals were similarly treated with these chemicals without the MNNG pretreatment. All rats were killed at the end of week 52 for histopathological examination. In the forestomach, treatment with catechol alone after MNNG initiation caused a 100% incidence of papillomas (versus 67% in the controls) as well as carcinomas (versus 0% in the controls). On the other hand, the treatment with ethanol alone significantly lowered the incidence of papillomas (13 versus 67% in the controls). The combined treatment with catechol, NaCl and ethanol significantly lowered the incidence of squamous cell carcinomas (57%) as compared to the catechol alone group value (100%). In the glandular stomach, catechol enhanced the development of adenocarcinomas (73 versus 0% in the controls), but this was decreased to 29% by the combined treatment with ethanol and NaCl. NaCl without MNNG pretreatment slightly enhanced epithelial cell proliferation in the forestomach. These results indicate that combined treatment with NaCl and ethanol exerts protective effects against catechol-induced forestomach and glandular stomach carcinogenesis, this apparently being largely due to the ethanol.

Topics: Animals; Body Weight; Carcinogenicity Tests; Catechols; Eating; Ethanol; Liver; Male; Methylnitronitrosoguanidine; Organ Size; Rats; Rats, Inbred F344; Sodium Chloride; Stomach Neoplasms

The susceptibility of pepsinogen-altered pyloric glands (PAPG) and neoplastic glandular stomach lesions induced by N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and catechol or sodium cholate in Nagase analbuminemic rats (NAR) was compared to Sprague-Dawley rats (SD). Male NAR and SD rats were given a single dose of 80 mg/kg body weight of MNNG by gastric intubation and, 2 weeks later, fed basal diet containing 0.8% catechol or 0.3% sodium cholate for 18 weeks. The animals were killed at the end of week 20 or after maintenance on basal diet at week 60. The number of pepsinogen-altered pyloric glands at week 20 was significantly (P < 0.001) higher in NAR fed either catechol or sodium cholate compared with SD rats. At week 60, adenomatous hyperplasias and adenocarcinomas were observed in 7 (88%; P < 0.01) and 3 (38%; P < 0.01) of 8 NAR fed catechol and in 4 (22%) and 0 of 18 SD rats, respectively. The results show that the frequency of PAPG in NAR and SD rats is related to the susceptibility to glandular stomach carcinoma. PAPG is a useful endpoint lesion for evaluation of gastric carcinogenicity in a 20-week carcinogenicity test, and NAR are sensitive for glandular stomach carcinogenesis.

Topics: Adenocarcinoma; Animals; Carcinogens; Catechols; Cholic Acid; Cholic Acids; Gastric Mucosa; Hyperplasia; Male; Methylnitronitrosoguanidine; Pepsinogens; Pyloric Antrum; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Serum Albumin; Species Specificity; Stomach Neoplasms

The effects of combined treatment with NaNO2 and phenolic compounds on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. In the first experiment, groups of 15-20 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 wk later, were given 2.0% butylated hydroxyanisole, 0.8% catechol, 2.0% 3-methoxycatechol or basal diet either alone or in combination with 0.2% NaNO2 in the drinking water until they were killed at week 52. All three antioxidants significantly enhanced forestomach carcinogenesis without any effect of additional NaNO2 treatment. However, in the absence of MNNG pretreatment, the grade of forestomach hyperplasia in the catechol and 3-methoxycatechol groups was significantly increased by the combined treatment with NaNO2. In a second experiment, the combined effects of various phenolic compounds and NaNO2 on cell proliferation in the upper digestive tract were examined. Groups of 5 rats were given one of 24 phenolic compounds or basal diet either alone or in combination with 0.3% NaNO2 for 4 weeks and then killed. Particularly strong enhancing effects in terms of thickness of the forestomach mucosa were seen with t-butylhydroquinone (TBHQ), catechol, gallic acid, 1,2,4-benzenetriol, dl-3-(3,4-dihydroxyphenyl)-alanine and hydroquinone in combination with NaNO2. In the glandular stomach, similar enhancing effects were evident in 11 cases, and in the esophagus with phenol, TBHQ and gallic acid. These results demonstrate that NaNO2 can augment cell proliferation induced in the stomach epithelium by various phenolic compounds.

Topics: Animals; Butylated Hydroxyanisole; Carcinoma, Squamous Cell; Catechols; Cell Division; Hyperplasia; Male; Methylnitronitrosoguanidine; Phenols; Rats; Rats, Inbred F344; Sodium Nitrite; Stomach; Stomach Neoplasms

Topics: Animals; Anticarcinogenic Agents; Antioxidants; Benzodioxoles; Butylated Hydroxyanisole; Caffeic Acids; Carcinogens; Carcinoma; Catechols; Cell Division; Hydroquinones; Kidney Neoplasms; Male; Maleates; Methylnitronitrosoguanidine; Organ Specificity; Papilloma; Phenols; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms

The methylation patterns of the rat pepsinogen 1 (Pg1) gene in preneoplastic and neoplastic stomach lesions induced by genotoxic N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or the non-genotoxic carcinogen catechol were investigated. Male WKY/Ncrj rats were given MNNG in their drinking water (50 mg/l) for 30 weeks or 0.8% catechol throughout the experiment (60 weeks). MNNG induced Pg1 altered pyloric glands (PAPG), adenomatous hyperplasias and well-differentiated adenocarcinomas. Catechol also induced PAPG and adenomatous hyperplasias although cancers did not develop. Adenomatous hyperplasias and adenocarcinomas all consisted of gastric type cells resembling surface mucous cells or pyloric gland cells with little or no Pg1 expression. In MNNG-induced stomach cancers generally lacking Pg1, altered Pg1 gene methylation was observed with both CCGG and GCGC sites being methylated more than normal pyloric mucosa. MNNG or catechol-induced adenomatous hyperplasias also demonstrated essentially the same methylation changes in the CCGG, but not in the GCGC sites. In the mucosa containing PAPG in groups treated with MNNG or catechol the methylation patterns of the Pg1 gene were quite similar to those of normal pyloric mucosa, although the CCGG sites tended to demonstrate slightly increased methylation. The results suggest that the altered methylation of the Pg1 gene observed in stomach cancers is acquired early in the carcinogenic process and progressive methylation changes occur with tumor development.

Topics: Adenocarcinoma; Animals; Catechols; DNA; Gastric Mucosa; Hyperplasia; Male; Methylation; Methylnitronitrosoguanidine; Pepsinogens; Precancerous Conditions; Rats; Rats, Inbred WKY; Stomach; Stomach Neoplasms

Catechol and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are gastric carcinogens in rats. Catechol, sodium chloride and bile salts have enhancing effects on gastric carcinogenesis induced by MNNG in rats. The effects of these compounds on proliferation of pyloric mucosa cells in male F344 rats were examined immunohistochemically using bromodeoxyuridine (BrdU) and anti-BrdU monoclonal antibody. Rats were given MNNG (83 micrograms/ml in their drinking water), catechol (0.8% in their diet), sodium taurocholate (0.3% in their diet), sodium taurodeoxycholate (0.3% in their diet), or sodium chloride (10% in their diet or by intragastric administration of 1 ml of saturated solution once a week) for 4 weeks. All these treatments markedly enhanced cell proliferation of the pyloric epithelium, suggesting the importance of enhanced cell proliferation in the development of gastric cancer.

Topics: Animals; Bile Acids and Salts; Carcinogens; Catechols; Cell Division; DNA; Gastric Mucosa; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred F344; Sodium Chloride; Taurocholic Acid; Taurodeoxycholic Acid

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.

Topics: Animals; Anisoles; Antioxidants; Butylated Hydroxytoluene; Carcinoma in Situ; Carcinoma, Squamous Cell; Catechols; Male; Methylnitronitrosoguanidine; Phenols; Rats; Rats, Inbred F344; Stomach Neoplasms

Catechol (CAS: 120-80-9) is present in the environment, being a major industrial chemical as well as a major phenolic component of cigarette smoke. Continuous oral treatment of rats with 0.8% catechol for 51 weeks after a single intragastric dose of 150 mg/kg of N-methyl-N'-nitro-N-nitrosoguanidine strongly enhanced both forestomach and glandular stomach carcinogenesis. In addition, and more importantly, catechol alone induced adenocarcinoma and adenomatous hyperplasia in the pyloric region of the glandular stomach. These results clearly indicate that this environmental contaminant merits classification as an enhancer of forestomach and glandular stomach carcinogenesis with complete carcinogenic potential for the glandular stomach. Its significance for gastric tumor development in man requires elucidation.

Topics: Adenocarcinoma; Adenoma; Animals; Carcinogens, Environmental; Catechols; Cocarcinogenesis; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred F344; Stomach Neoplasms