Mechanism of carcinogenesis induced by a veterinary antimicrobial drug, nitrofurazone, via oxidative DNA damage and cell proliferation.
Nitrofurazone, a veterinary antimicrobial drug, causes mammary and ovarian tumors in animals. We investigated the mechanisms of carcinogenesis by nitrofurazone. Nitrofurazone significantly stimulated the proliferation of estrogen-dependent MCF-7 cells. Nitrofurazone caused Cu(II)-mediated damage to 32P-5'-end-labeled DNA fragments obtained from human genes only when cytochrome P450 reductase was added. DNA damage was inhibited by catalase and bathocuproine. DNA damage was preferably induced at the 5'-ACG-3' sequence, a hotspot of the p53 gene. These findings suggest that nitrofurazone metabolites are involved in tumor initiation through oxidative DNA damage and nitrofurazone itself enhances cell proliferation, leading to promotion and/or progression in carcinogenesis.
Hiraku
Yusuke
Y
Department of Environmental and Molecular Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
Sekine
Aki
A
Nabeshi
Hiromi
H
Midorikawa
Kaoru
K
Murata
Mariko
M
Kumagai
Yoshito
Y
Kawanishi
Shosuke
S
D000890:Anti-Infective Agents / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002273:Carcinogens; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D005609:Free Radicals / Q000378:metabolism; D016158:Genes, p53 / Q000187:drug effects; D006801:Humans; D009251:NADPH-Ferrihemoprotein Reductase / Q000494:pharmacology; D009376:Neoplasms, Hormone-Dependent; D009583:Nitrofurazone / Q000633:toxicity*; D010084:Oxidation-Reduction; D018384:Oxidative Stress
D000890:Anti-Infective Agents; D002273:Carcinogens; D005609:Free Radicals; D009251:NADPH-Ferrihemoprotein Reductase; D009583:Nitrofurazone