HIRAKU Yusuke Mie University, School of Medicine, Research Associate, 医学部, 助手 (30324510)
OIKAWA Shinji Mie University, School of Medicine, Assistant Professor, 医学部, 講師 (10277006)
MURATA Mariko Mie University, School of Medicine, Assistant Professor, 医学部, 講師 (10171141)
|Budget Amount *help
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2002: ¥6,200,000 (Direct Cost: ¥6,200,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥4,300,000 (Direct Cost: ¥4,300,000)
Sequence-specific DNA damage induced by oxidative stress plays the key role in carcinogenesis and aging. Therefore, study on its sequence specificity would provide us biological significance of DNA damage and beneficial findings for cancer prevention.
(1)Role of sequence-specific DNA damage by oxidative stress in carcinogenesis.
We investigated sequence specificity of DNA damage induced by BP-7,8-diol-9,10-epoxide, a carcinogenic benzo[α]pyrene metabolite, using ^<32>P-5'-end-labeled DNA. BP-7,8-dione strongly damaged G and C of the 5'-ACG-3' sequence complementary to codon 273(a hot spot) of the p53 gene. We concluded that oxidative DNA damage, especially double base lesions, may participate in the expression of carcinogenicity of BP in addition to DNA adduct formation. Furthermore, we demonstrated that in addition to DNA adduct formation, oxidative DNA damage may be involved in the carcinogenic process of polyaromatic amines. In addition, the monoaromatic amine, azo compounds, nitro co
mpounds, organic solvents, dietary factors and medical and pharmaceutical products also induced sequence-specific DNA damage via H_2O_2 generation. We demonstrated that UVA radiation caused DNA oxidation at GG sequences in the presence of photosensitizers(folic acid, xanthone, etc).
(2) Role of sequence-specific DNA damage by oxidative stress in aging.
We demonstrated that oxidative stress (H_2O_2, NO+O_2^-, UVA) specifically oxidizes guanine of 5'-GGG-3' in telomere sequence to produce 8-oxodG. The terminal restriction fragment (TRF) from WI-38 fibroblasts irradiated with UVA decreased with increasing the irradiation doses. It is concluded that the site-specific damage in telomere sequence induced by oxidative stress may participate in an increase of telomere shortening rate, leading to acceleration of aging.
(3) Safety evaluation of chemopreventive agents.
We found that antioxidants (quercetin, isothiocyanates, curcumin, etc) can serve as prooxidants, capable of causing carcinogenesis via oxidative DNA damage. On the other hand, phytic acid does not cause DNA damage and can be potential cancer chemopreventive agent. Less