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Modulation of Oxidant Formation in Mouse Skin in Vivo by Tumor-promoting Phorbol Esters¹

A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146

The pathways of oxidant generation in mouse epidermis were investigated by ³²P-postlabeling analysis of diastereomeric DNA adducts derived from oxidation of (7S,8S)-dihydroxy-7,8-dihydrobenzo(a)pyrene ((+)-BP-7,8-diol). The pattern of deoxynucleoside-3'-5'-bis-phosphate adducts in epidermal scrapings from female CD-1 mice indicated that cytochrome P-450 was the major oxidant. When animals were pretreated with the tumor-promoting phorbol ester, tetradecanoyl phorbol acetate (TPA), 24 h before coadministration of TPA and (+)-BP-7,8-diol, the pattern of DNA adducts indicated that peroxyl radicals made a major contribution to (+)-BP-7,8-diol epoxidation. Peroxyl radical-dependent epoxidation was maximal when the time between the 2 TPA administrations was 24–72 h. No increase in radical-derived adducts was observed when the non-tumor-promoting phorbol ester 4-O-methyl-TPA was substituted for TPA. The calcium ionophore A23187 stimulated radical generation when substituted for the first, but not the second, TPA treatment. The antiinflammatory steroid fluocinolone acetonide inhibited (-)-anti-BPDE-DNA adduct formation when coadministered with the first but not the second TPA treatment. In contrast, all-trans-retinoic acid inhibited (-)-anti-BPDE-DNA adduct formation when coadministered with the second but not the first TPA treatment. These findings demonstrate that tumor promoting phorbol esters stimulate oxygen radical generation in mouse skin and that radical generation is blocked by inhibitors of tumor promotion.

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