Cell proliferation and forestomach carcinogenesis.

To analyze the role of cell proliferation in phenolic compound-induced rat forestomach carcinogenesis, early forestomach histopathological changes as well as oncogene expression and reversibility of early forestomach lesions were examined in F344 male rats. For the analysis of early lesions, five animals each were treated with butylated hydroxyanisole (BHA), caffeic acid, sesamol, or 4-methoxyphenol in the diet, each at a dose of 2%, and killed for histopathological examination after 12 hr, 1, 3, or 7 days. For oncogene analysis, three animals each were treated with BHA for 15, 30 min, 1, 3, 6, or 24 hr and then sacrificed. In the reversibility study, groups of animals were treated with BHA, caffeic acid, sesamol or 4-methoxyphenol for 24 weeks, and basal diet alone was supplied for a further 24-week period. Animals were killed at 24 and 48 weeks and forestomach epithelium was examined histopathologically. DNA synthesis increased within 12 hr to 3 days after commencement of chemical treatment in all cases. Toxicity and cell proliferation became evident subsequent to increase in DNA synthesis in each case. Elevated expression of c-fos and c-myc oncogenes was demonstrated 15 min after beginning treatment with BHA. In the reversibility study, although most of the proliferative lesions induced by these antioxidants regressed after cessation of chemical treatment, some dysplastic lesions were still observed at week 48. The results indicate that these phenolic compounds act primarily as mitogens in rat forestomach epithelium, with regeneration due to toxicity further enhancing cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)