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Pro/antioxidant status in murine skin following topical exposure to cumene hydroperoxide throughout the ontogeny of skin cancer.

Abstract
Organic peroxides used in the chemical and pharmaceutical industries have a reputation for being potent skin tumor promoters and inducers of epidermal hyperplasia. Their ability to trigger free radical generation is critical for their carcinogenic properties. Short-term in vivo exposure of mouse skin to cumene hydroperoxide (Cum-OOH) causes severe oxidative stress and formation of spin-trapped radical adducts. The present study was designed to determine the effectiveness of Cum-OOH compared to 12-O-tetradecanoylphorbol-13-acetate (TPA) in the induction of tumor promotion in the mouse skin, to identify the involvement of cyclooxygenase-2 (COX-2) in oxidative metabolism of Cum-OOH in keratinocytes, and to evaluate morphological changes and outcomes of oxidative stress in skin of SENCAR mice throughout a two-stage carcinogenesis protocol. Dimethyl-benz[a]anthracene (DMBA)-initiated mice were treated with Cum-OOH (32.8 micro mol) or TPA (8.5 nmol) twice weekly for 20 weeks to promote papilloma formation. Skin carcinoma formed only in DMBA/Cum-OOH-exposed mice. Higher levels of oxidative stress and inflammation (as indicated by the accumulation of peroxidative products, antioxidant depletion, and edema formation) were evident in the DMBA/Cum-OOH group compared to DMBA/TPA treated mice. Exposure of keratinocytes (HaCaT) to Cum-OOH for 18 h resulted in expression of COX-2 and increased levels of PGE(2). Inhibitors of COX-2 efficiently suppressed oxidative stress and enzyme expression in the cells treated with Cum-OOH. These results suggest that COX-2-dependent oxidative metabolism is at least partially involved in Cum-OOH-induced inflammatory responses and thus tumor promotion.
AuthorsA A Shvedova, E R Kisin, A Murray, C Kommineni, V Vallyathan, V Castranova
JournalBiochemistry. Biokhimiia (Biochemistry (Mosc)) Vol. 69 Issue 1 Pg. 23-31 (Jan 2004) ISSN: 0006-2979 [Print] United States
PMID14972014 (Publication Type: Journal Article)
Chemical References
  • Antioxidants
  • Benzene Derivatives
  • Enzyme Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • Sulfhydryl Compounds
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Glutathione
  • Dinoprostone
  • Tetradecanoylphorbol Acetate
  • cumene hydroperoxide
Topics
  • Animals
  • Antioxidants (metabolism)
  • Benzene Derivatives (toxicity)
  • Cell Line, Tumor
  • Cyclooxygenase 2
  • Dinoprostone (metabolism)
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Glutathione (metabolism)
  • Humans
  • Inflammation (metabolism)
  • Isoenzymes (antagonists & inhibitors, metabolism)
  • Keratinocytes (drug effects, metabolism, pathology)
  • Lipid Peroxidation (drug effects)
  • Membrane Proteins
  • Mice
  • Mice, Inbred SENCAR
  • Oxidative Stress (drug effects)
  • Prostaglandin-Endoperoxide Synthases (metabolism)
  • Skin Neoplasms (chemically induced, metabolism, pathology)
  • Sulfhydryl Compounds (metabolism)
  • Tetradecanoylphorbol Acetate (toxicity)

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