Tumor promotion by a hydroxyperoxide metabolite of butylated hydroxytoluene, 2,6-di-tert-butyl-4-hydroperoxy-4-methyl-2,5-cyclohexadienone, in mouse skin

The nature of the skin tumor promotion response to a hydroperoxide metabolite of butylated hydroxytoluene, 2,6-di-tert-butyl-4-hydroperoxyl-2,5-cyclohexadienone (BHTOOH), was examined in SENCAR mice. BHTOOH was an effective inducer of epidermal ornithine decarboxylase (ODC) activity. Maximal induction of ODC activity was observed 12 hours after a single application of BHTOOH. Dose-dependent increases were seen between 2 and 20 μmol while higher amounts were less effective. A similar dose-response relationship for papilloma and carcinoma formation was observed when BHTOOH was applied twice weekly for 50 weeks to mice previously initiated with 7,12-dimethylbenz[a]anthracene. Doses of 2, 8, and 20 μmol BHTOOH gave maximal papilloma responses of 0.1, 0.6, and 3.6 papillomas/mouse, respectively. The progression of papillomas to carcinomas was examined and at 60 weeks the incidence of carcinomas was 0, 17, and 28% for the three treatment groups. The carcinoma:papillloma ratios were 0.08 and 0.40 for the high and intermediate BHTOOH dose groups. The data suggest that BHTOOH, unlike butylated hydroxytoluene, is an effective tumor promoter in mouse skin. Additionally, BHTOOH may enhance the conversion of papillomas to carcinomas. However, BHTOOH is not a complete carcinogen in that no papillomas or carcinomas were observed in uninitiated mice treated with BHTOOH only.