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

Abstract

The effects of sodium nitrite (NaNO 2), 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% NaNO 2 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 NaNO 2 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 NaNO 2 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 NaNO 2 groups than in the single compound groups. In rats without MNNG treatment, combined treatment of antioxidants with NaNO 2 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 NaNO 2 caused significant increase. These results indicate that co-administration of NaNO 2 with α-Toc, TBHQ or PG and particularly the first, promotes forestomach carcinogenesis. Concurrent α-Toc, TBHQ or PG treatment with NaNO 2 is likely to induce forestomach tumors in the long term.