INDUCTION OF 5,6-RING-SATURATED THYMINE BASES IN NIH-3T3 CELLS BY PHORBOL ESTER-STIMULATED MACROPHAGES - ROLE OF REACTIVE OXYGEN INTERMEDIATES

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (3) , 1270-1275
Abstract
Because O2 intermediates secreted by inflammatory leukocytes are postulated to play a role in potentiating carcinogenesis, the ability of macrophages to induce oxidative DNA damage in eukaryotic cells was studied. Murine macrophages, obtained from sites of inflammation and stimulated with 12-O-tetradecanoylphorbol-15-acetate, induced the formation of 5,6-ring-saturated thymine bases in the DNA of cocultured NIH-3T3 cells; macrophages or 12-O-tetradecanoylphorbol-15-acetate alone did not induce such alterations. Reagent H2O2, at concentrations produced by macrophages in the ambient medium (i.e., .apprx. 10-5 M), induced saturated thymines in the target cells in a dose-dependent manner. The reaction between reagent H2O2 and cellular DNA was rapid, reaching maximium levels in 30 min and similar amounts of saturated thymines were induced at 4.degree. or 37.degree.. The 3T3 targets were able to repair the saturated thymines rapidly (i.e., over 70% of the lesion was removed in 2 h). Catalase completely inhibited macrophage-mediated induction of saturated thymines, although superoxide dismutase enhanced induction. Macrophages exposed to phorbol diesters evidently can induce a specific, quantifiable lesion in the DNA of bystander eukaryotic cells. Reactive oxygen species from the macrophages probably participate in producing the lesion.

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