DNA single- and double-strand breaks produced by ferric nitrilotriacetate in relation to renal tubular carcinogenesis.
Fe(III) bound to a chelator, nitrilotriacetate (NTA), has been reported to induce a high frequency of adenocarcinoma localized to the proximal tubules of the kidney in rodents. In order to examine possible mechanisms for the carcinogenic activity, we investigated the in vitro production of single- and double-strand breaks in DNA mediated by iron alone or Fe-NTA chelate using supercoiled plasmid pZ189. Neither Fe(III) nor NTA alone broke DNA. Fe(III) plus NTA together mediated the efficient oxidative production of DNA single- and double-strand breaks in the presence of reducing agents (ascorbate >> H2O2 > cysteine). The Fe(III):NTA ratio (1:4) that was found to be optimal for DNA strand breakage was similar to the ratio that produced adenocarcinomas in rodents. Maximal Fe-NTA-mediated DNA damage in vitro was induced under conditions of neutral pH, low ionic strength, presence of reducing agent and absence of albumin. These conditions are present exclusively in the cortical proximal tubules of the kidney, the only location where toxicity and carcinogenicity of Fe-NTA has been observed. Thus, localized DNA damage may explain the anatomic site preferred by Fe-NTA-induced carcinogenesis.
Toyokuni
S
S
Division of Life Sciences, Office of Science and Technology, Center for Devices and Radiological Health, Food and Drug Administration, Rockville, MD 20857.
Sagripanti
J L
JL
D000230:Adenocarcinoma / Q000139:chemically induced*; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004270:DNA, Circular / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000187:drug effects; D004278:DNA, Superhelical / Q000187:drug effects; D005290:Ferric Compounds / Q000633:toxicity*; D006861:Hydrogen Peroxide / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007680:Kidney Neoplasms / Q000139:chemically induced*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology; D007700:Kinetics; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D010957:Plasmids
D004270:DNA, Circular; D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; D005290:Ferric Compounds; D004247:DNA; D006861:Hydrogen Peroxide; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate