Activation of AP-1 and pro/antioxidant status in skin of AP-1 transgenic mice during cancer promotion with cumene hydroperoxide.
Xu-M; Kisin-E; Murray-AR; Kommineni-C; Vallyathan-V; Castranova-V; Shvedova-AA
Toxicologist 2004 Mar; 78(S-1):338
Organic peroxides, widely used in the chemical and pharmaceutical industries, can act as skin tumor promoters and cause epidermal hyperplasia. They are also known to trigger free radical generation. The present study evaluated the effect of cumene hydroperoxide (Cum-OOH) on the induction of activator protein-1 (AP-1), which is linked to the expression of genes regulating cell proliferation, growth, and trans-formation. Previously, we reported that topical exposure to Cum-OOH caused formation of free radicals and oxidative stress in skin of vitamin E deficient mice. In addition, in vitro studies found that exposure to Cum-OOH reduced levels of GSH in JB6 P + cells and caused the induction of AP-1. The present study used AP-1-luciferase reporter transgenic mice to identify whether exposure to Cum-OOH in vivo caused activation of AP-1, oxidative stress, depletion of antioxidants and tumor formation during two-stage carcinogenesis. Mice primed with dimethyl-benz[a]anthracene (DMBA) were treated topically with Cum-OOH (82.6 umol) or 12-O-tetradecanoylphorbol-13-acetate (TPA, 17 nmol) twice weekly for 20 weeks. Activation of AP-1 in skin was detected as early as 2 weeks following Cum-OOH and TPA exposures. Maximum AP-1 expression was detected 4 weeks post initiation with Cum-OOH or TPA. No AP-1 activation was found 19 weeks post initiation. Papilloma formation was observed in both the DMBA/TPA and DMBA/Cum-OOH exposed animals, while skin carcinomas were found only in the DMBA/Cum-OOH treated mice. A greater accumulation of peroxidative products (TBARS), inflammation, and decreased levels of GSH, vitamin E and total antioxidant reserves were also observed in the skin of DMBA/Cum-OOH exposed mice. These results suggest that Cum-OOH induced carcinogenesis is accompanied by increased AP-1 activation and changes in antioxidant status.
Antioxidants; Antioxidation; Laboratory-animals; Animal-studies; Animals; Cancer; Organic-peroxides; Peroxides; Skin-tumors; Skin-cancer; Genes; Exposure-levels; Stress; In-vitro-studies; Carcinogenesis; In-vivo-studies
Disease and Injury: Allergic and Irritant Dermatitis
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland