Evidence that ferric nitrilotriacetate mediates oxidative stress by down-regulating DT-diaphorase activity: implications for carcinogenesis

Ferric nitrilotriacetate (Fe-NTA) is a known complete renal carcinogen as w ell as renal and hepatic tumor promoter, which acts by generating oxidative stress in the tissue. However, the mechanism by which it generates this st ress is not fully understood. In this study, we show that Fe-NTA down-regul ates hepatic and renal quinone reductase (QR) activity dose dependently. Th e maximum decrease in the activity of QR was observed at 12 h in the liver and 6 h in the kidney following Fe-NTA treatment. However, at all other tim e points studied, QR activity was reduced. In addition, a parallel increase in protein carbonyl content, a sensitive indicator of tissue oxidative str ess was observed both in the liver and kidney. The pretreatment of animals with antioxidants. butylated hydroxyanisole and butylated hydroxytoluene, p revented the observed inhibition in the activity of QR and enhanced the for mation of protein carbonyl in both organs. These studies suggest that Fe NT A-mediated generation of oxidant free radicals down-regulates QR activity w hich may be responsible, at least in part, for the observed renal and hepat ic injury and carcinogenic properties of Fe-NTA. (C) 1999 Published by Else vier Science Ltd. All rights reserved.