Oxidatively generated DNA damage induced by 3-amino-5-mercapto-1,2,4-triazole, a metabolite of carcinogenic amitrole.
Amitrole (3-amino-1,2,4-triazole) is a widely used herbicide. Amitrole induces thyroid and liver tumors in rodents. However, the mechanism of carcinogenesis by amitrole remains to be clarified. To clarify the mechanism of carcinogenesis induced by amitrole, we investigated the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic of oxidatively generated DNA damage, by an amitrole metabolite, 3-amino-5-mercapto-1,2,4-triazole (AMT), in the presence of Cu(II). The amount of 8-oxodG was increased by AMT in the presence of Cu(II). AMT-induced 8-oxodG formation was enhanced in deuterium oxide (D₂O), which prolongs the half life of singlet oxygen (¹O₂), more than that in H₂O. Sodium azide and 1,4-diazabicyclo[2,2,2]-octane (DABCO), potent and relatively specific scavengers of ¹O₂, inhibited AMT-mediated 8-oxodG formation. Bathocuproine, a Cu(I) chelator, also inhibited the 8-oxodG formation. On the other hand, typical OH scavengers did not inhibit the generation of 8-oxodG. AMT plus Cu(II) also induced piperidine-labile DNA lesions frequently at every guanine residue. These results suggest that ¹O₂ and Cu(I) play an important role in DNA damage induced by AMT. It is concluded that oxidatively generated DNA damage induced by AMT via the generation of ¹O₂ may contribute to carcinogenicity of amitrole.
Furukawa
Ayako
A
Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, Aichi 480-0392, Japan.
Oikawa
Shinji
S
Harada
Kanako
K
Sugiyama
Hirokazu
H
Hiraku
Yusuke
Y
Murata
Mariko
M
Shimada
Atsuyoshi
A
Kawanishi
Shosuke
S
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000640:Amitrole / Q000031:analogs & derivatives*; D002273:Carcinogens; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced; D009363:Neoplasm Proteins / Q000235:genetics; D010100:Oxygen / Q000737:chemistry*; D010618:Phenanthrolines / Q000494:pharmacology; D019810:Sodium Azide / Q000737:chemistry; D013964:Thyroid Neoplasms / Q000139:chemically induced; D014230:Triazoles / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
C488155:3-amino-5-mercapto-1,2,4-triazole; C000614131:CDKN2A protein, human; D002273:Carcinogens; D002614:Chelating Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D010618:Phenanthrolines; C495901:TP53 protein, human; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019810:Sodium Azide; C002478:bathocuproine; D018631:ras Proteins; D003849:Deoxyguanosine; D010100:Oxygen; D000640:Amitrole