Promoting effects of combined antioxidant and sodium nitrite treatment on forestomach carcinogenesis in rats after initiation with N-methyl-N′-nitro-N-nitrosoguanidine

The effects of sodium nitrite (NaNO2), in combination with one of three antioxidants, tert-butylhydroquinone (TBHQ), α-tocopherol (α-Toc) and propyl gallate (PG), on N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) stomach carcinogenesis were investigated in F344 rats. Groups of 15 male rats were treated with an intragastric dose of 150 mg/kg body weight of MNNG, and starting 1 week later, were treated with 0.5% TBHQ, 1% α-Toc, 1% PG or basal diet with or without 0.2% NaNO2 in their drinking water until they were killed at the end of week 36. Macroscopically, in MNNG-treated animals, combined administration of α-Toc or PG with NaNO2 significantly increased the areas and numbers of forestomach nodules as compared with the respective antioxidant alone values. Microscopically, in MNNG-treated animals, treatment with TBHQ significantly increased the incidence and multiplicity of forestomach papillomas as compared with basal diet alone value. Combined administration of α-Toc with NaNO2 significantly raised the multiplicity of forestomach papillomas, with a tendency to elevation in the incidence as compared with the group given α-Toc alone. Incidences of forestomach moderate and/or severe hyperplasias were significantly higher in the TBHQ or PG plus NaNO2 groups than in the single compound groups. In rats without MNNG treatment, combined treatment of antioxidants with NaNO2 significantly increased the incidences of mild or moderate hyperplasia. In the glandular stomach, although the incidence of atypical hyperplasia showed a non-significant tendency for decrease with TBHQ treatment, additional administration of NaNO2 caused significant increase. These results indicate that co-administration of NaNO2 with α-Toc, TBHQ or PG and particularly the first, promotes forestomach carcinogenesis. Concurrent α-Toc, TBHQ or PG treatment with NaNO2 is likely to induce forestomach tumors in the long term.