ASSESSMENT OF THE ANTIOXIDANT PROOXIDANT STATUS OF MURINE SKIN FOLLOWING TOPICAL TREATMENT WITH 12-O-TETRADECANOYLPHORBOL-13-ACETATE AND THROUGHOUT THE ONTOGENY OF SKIN-CANCER .1. QUANTITATION OF SUPEROXIDE-DISMUTASE, CATALASE, GLUTATHIONE-PEROXIDASE AND XANTHINE-OXIDASE

The activities of several enzymes involved in reactive oxygen production and detoxification were quantified in murine skin during the ontogeny of chemically induced skin cancer. Relative to solvent-treated controls, the specific activities of epidermal superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) were reduced approximately 45, approximately 60 and approximately 24% respectively, 24 h after the fourth or tenth topical application of 1-mu-g of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal skin of SENCAR mice. The specific activity of epidermal xanthine oxidase (XO) increased approximately 350% during the same period. SOD and CAT specific activities in papillomas and carcinomas generated in an initiation-promotion protocol were approximately 15 and approximately 40% respectively of the activities measured in age-matched, non-treated mice. CAT and SOD activities were also significantly suppressed in the skin adjacent to the papillomas for several weeks following the cessation of TPA promotion, but eventually recovered to the levels measured in age-matched controls. XO specific activities in papillomas and squamous cell carcinomas (SCC) were approximately 85-350% greater than the activities determined in skin adjacent to the tumors. The increases in XO and the decreases in SOD and CAT activities measured in the tumors were independent of continued treatment with TPA, and thus characteristic of the tumor phenotype. GPX activities in papillomas were comparable to normal, untreated skin, but reduced approximately 22-41% in SCC. Collectively, these studies demonstrate that TPA orchestrates changes in the activities of several enzymes involved in reactive oxygen metabolism that are characteristic of the papilloma and SCC phenotype.