|Budget Amount *help
¥12,800,000 (Direct Cost : ¥12,800,000)
Fiscal Year 1999 : ¥1,700,000 (Direct Cost : ¥1,700,000)
Fiscal Year 1998 : ¥3,800,000 (Direct Cost : ¥3,800,000)
Fiscal Year 1997 : ¥7,300,000 (Direct Cost : ¥7,300,000)
We have investigated the mechanisms of direct DNA damage induced by environmental factors and indirect DNA damage mediated by nitric oxide (NO) and reactive oxygen species released from inflammatory cells, such as monocytes and neutrophils. The main findings in this study are summarized as follows. (1) As dietary factors, heterocyclic amines and amino acid metabolite caused DNA damage in the presence of metal ions. Antioxidants, such as β-carotene, vitamin E (α-tocophorol), N-acetylcystein and flavonoids, induced oxidative DNA damage in the presence of metal ions, suggesting that these antioxidants can act as prooxidants. Benzoyl peroxide, a food additive, induced sequence-specific DNA damage at the 5'G of GG sequence in the presence of Cu(I). As occupational and air pollutant factors, metabolites of toluene, o-toluidine and nitrobenzene, which may be associated with occupational cancer, caused DNA damage mediated by photoactivation of endogenous molecules. In addition, a quinolone antibacterials, nalidixic acid and lomefloxacin caused DNA photodamage through electron transfer and the generation of singlet oxygen, respectively. This findings suggests that these drugs can act as exogenous photocarcinogens.(3) Concerning indirect DNA damage by inflammatory factors, oxidative DNA damage in human cultured cells was induced by simultaneous generation of NO superoxide (OィイD22ィエD2ィイD1-ィエD1). The formation of 8-oxodG in cultured cells was significantly increased by exposure to NO released from macrophages activated by carcinogenic nickel compounds, indicating that inflammation can mediate DNA damage through an indirect mechanism. On the basis of these findings, carcinogenesis induced by environmental factors involves direct DNA damage mediated by oxidative stress and indirect DNA damage mediated by inflammatory cells.