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Activated inflammatory leukocytes generate a variety of reactive oxygen and nitrogen species (RONS) that may have roles in mutagenesis and carcinogenesis. The purpose of the present study was to explore the relationship between inflammatory leukocyte activation and mutagenesis using co-culture systems. We investigated the mutagenic potentials of 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated differentiated HL-60 (human promyelocytic leukemia cells), and RAW 264.7 cells (murine macrophages) stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma by co-culturing each cell line with AS52 cells, a transgenic Chinese hamster ovary cell line. HL-60 cells rapidly generated superoxide (O(2)(-)) 15 min to 1 h (peak at 30 min) following TPA stimulation. RAW 264.7 cells stimulated with LPS and IFN-gamma produced O(2)(-), nitric oxide (NO) and peroxynitrite (ONOO(-)) continuously for 5-25 h. There was a 2.0-fold increase in the mutation frequency of the gpt gene in AS52 cells co-cultured with TPA stimulated HL-60 cells, when compared with non-treated cells. Importantly, this increase in mutation frequency was significantly suppressed by antioxidants, such as superoxide dismutase (SOD) and diphenylene iodonium (DPI), an NADPH oxidase inhibitor (inhibition rates: IRs = 18.2 and 35.1%, respectively). Similarly, co-culture of AS52 cells with LPS/IFN-gamma-stimulated RAW 264.7 cells also increased the mutation frequency of the gpt gene by 2.6-fold, and this increase in mutation frequency was suppressed by SOD, DPI and N(5)-(1-iminoethyl)-L-ornithine dihydrochloride (L-NIO), an specific iNOS inhibitor (IRs = 58.3, 70.8 and 70.8%, respectively). In co-culture experiments, activated HL-60 and RAW 264.7 cells increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in AS52 cells when compared with non-treated controls (1.7- and 1.6-fold, respectively). Treatment of AS52 cells with hydrogen peroxide (H(2)O(2), 100 micro M), ONOO(-) (100 micro M) and SIN-1 (100 micro M), a ONOO(-) generator, also increased the mutation frequency of the gpt gene (4.6-, 5.4- and 2.8-fold, respectively). Taken together, these results support the hypothesis that RONS, derived from activated inflammatory leukocytes, are mutagenic in the biological systems, and that RONS generation inhibitors are potentially anti-mutagenic, and thus may be useful in cancer preventive strategies.

Mutagenicity of reactive oxygen and nitrogen species as detected by co-culture of activated inflammatory leukocytes and AS52 cells