Oxidatively generated DNA damage induced by 3-amino-5-mercapto-1,2,4-triazole, a metabolite of carcinogenic amitrole.

Abstract

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.

• Authors: Ayako Furukawa, Shinji Oikawa, Kanako Harada, Hirokazu Sugiyama, Yusuke Hiraku, Mariko Murata, Atsuyoshi Shimada, Shosuke Kawanishi
• Journal: Mutation research (Mutat Res) Vol. 694 Issue 1-2 Pg. 7-12 (Dec 10 2010) ISSN: 0027-5107 [Print] Netherlands
• PMID: 20732334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• 3-amino-5-mercapto-1,2,4-triazole
• CDKN2A protein, human
• Carcinogens
• Chelating Agents
• Cyclin-Dependent Kinase Inhibitor p16
• Neoplasm Proteins
• Phenanthrolines
• TP53 protein, human
• Triazoles
• Tumor Suppressor Protein p53
• Copper
• 8-Hydroxy-2'-Deoxyguanosine
• Sodium Azide
• bathocuproine
• ras Proteins
• Deoxyguanosine
• Oxygen
• Amitrole

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Amitrole (analogs & derivatives)
• Carcinogens
• Chelating Agents (pharmacology)
• Copper (chemistry)
• Cyclin-Dependent Kinase Inhibitor p16
• DNA Damage
• Deoxyguanosine (analogs & derivatives, metabolism)
• Humans
• Liver Neoplasms (chemically induced)
• Neoplasm Proteins (genetics)
• Oxygen (chemistry)
• Phenanthrolines (pharmacology)
• Sodium Azide (chemistry)
• Thyroid Neoplasms (chemically induced)
• Triazoles (adverse effects)
• Tumor Suppressor Protein p53 (genetics)
• ras Proteins (genetics)