Oxidative DNA damage induced by photodegradation products of 3(')-azido-3(')-deoxythymidine.
3(')-Azido-3(')-deoxythymidine (AZT) is carcinogenic to experimental animals and can cause the formation of 8-oxo-7,8-dihydro-2(')-deoxyguanosine (8-oxodG) in humans and animals. To clarify the mechanism of carcinogenesis by AZT, we investigated DNA damage induced by its photodegradation products, using 32P-5(')-end-labeled DNA fragments obtained from human genes. Following exposure to UVB, AZT induced DNA damage in the presence of Cu(II). Catalase inhibited DNA damage, indicating the involvement of H(2)O(2). UVB-exposed AZT plus Cu(II) induced 8-oxodG formation in a dose-dependent manner. Mass spectrum of UVB-exposed AZT demonstrated the generation of a hydroxylamine derivative. The colorimetric determination suggested that AZT was converted into the hydroxylamine derivative depending on UVB doses. UVB-exposed AZT induced double base damage at the 5(')-ACG-3(') sequence, complementary to a hot spot of the p53 gene. The basic compound, hydroxylamine, showed similar site specificity. The hydroxylamine derivative produced by photodegradation and/or possible metabolism of AZT induces oxidative DNA damage, which may participate in carcinogenesis.
Iwamoto
Takuya
T
Department of Environmental and Molecular Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Hiraku
Yusuke
Y
Oikawa
Shinji
S
Mizutani
Hideki
H
Kojima
Michio
M
Kawanishi
Shosuke
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002417:Cattle; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives*; D019942:Genes, p16; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010777:Photochemistry / Q000379:methods; D014466:Ultraviolet Rays; D015215:Zidovudine / Q000737:chemistry* / Q000528:radiation effects*
D015215:Zidovudine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C427203:calf thymus DNA; D003849:Deoxyguanosine