Abstract
The characteristics of non-genotoxic phenolic compound-induced rat forestomach carcinogenesis were analysed. The incidence of forestomach lesions did not increase with BHA pretreatment, but was elevated when BHA or caffeic acid was administered after N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) initiation in the 2-step rat forestomach carcinogenesis model. Induction of forestomach tumors was also strongly enhanced by BHA given together with genotoxic carcinogens such as methylnitrosourea (MNU), 3, 2'-dimethyl-4-aminobiphenyl (DMAB) or 2, 2'-dihydroxy-di-n-propyl-nitrosamine (DHPN) as compared to with these carcinogens alone. DNA synthesis in the forestomach epithelium increased within 12 hr to 3 days after commencement of chemical treatment in all cases. Toxicity (inflammation and erosion or ulceration) and cell proliferation became evident subsequent to increase in DNA synthesis in each case. Elevated expression of c-for and c-myc oncogenes in the forestomach epithelium was demontrated 15 min after beginning treatment with BHA, caffeic acid or 4-methoxyphenol. In a reversibility study, although most of the proliferative lesions in the forestomach epithelium induced by these antioxidants regressed after cessation of chemical treatment, some dysplastic lesions were still observed at week 48. The results indicated that these non-genotoxic phenolic compounds possess strong promoting activity, primarily acting as mitogens in rat forestomach epithelium, with regeneration due to toxicity further enhancing cell proliferation. During this continuous elevation of cell turnover, dysplastic lesions appear which persist and presumably play a role in the eventual development of forestomach carcinomas.
