Ferric nitrilotriacetate promotes N-diethylnitrosamine-induced renal tumorigenesis in the rat: Implications for the involvement of oxidative stress

Academic Article

Abstract

  • Ferric nitrilotriacetate (Fe-NTA) is a known complete renal carcinogen. In this study we show that Fe-NTA is a potent inducer of renal ornithine decarboxylase (ODC) activity and DNA synthesis and promoter of N-diethylnitrosamine (DEN)-induced renal tumorigenesis in rat. Fe-NTA induced renal ODC activity several fold as compared with salinetreated rats. Renal DNA synthesis, measured as [3H]thymidine incorporation into DNA, was increased after Fe-NTA treatment. Similar to other known tumor promoters, Fe-NTA also depleted the antioxidant armory of the tissue. It depleted glutathione (GSH) levels to ~ 55% of saline-treated controls. It also led to a dose-dependent decrease in the activities of glutathione reductase and glutathione S-transferase. Similarly, activities of catalase, glutathione peroxidase and glucose 6-phosphate dehydrogenase decreased significantly (45-65%). In contrast, γ-glutamyl transpeptidase activity showed an increase. The maximum changes in activities of these enzymes could be observed at 12 h following Fe-NTA treatment. In addition, Fe-NTA augmented renal microsomal lipid peroxidation > 150% over saline-treated controls, which was concomitant with the alterations in GSH metabolizing enzymes and depletion of the antioxidant armory. These effects were alleviated in rats which received a pretreatment with an antioxidant, BHA or BHT. Fe-NTA promoted DEN-induced renal tumorigenesis. In saline alone- and DEN alone-treated animals no tumors could be recorded, whereas in Fe-NTA alone-treated animals 17% tumor incidence was observed. However, in DEN-initiated and Fe-NTA-promoted animals tumor incidence increased to 71%. Our results show that Fe-NTA induces oxidative stress in the kidney and decreases antioxidant defenses, as indicated by the fall in GSH level and in the activities of glutathione peroxidase and catalase. Concomitantly, Fe-NTA increases ODC activity and DNA synthesis, which may be compensatory changes following oxidative injury to renal cells in addition to providing a strong stimulus for renal tumor promotion. Thus oxidative stress and impaired antioxidant defenses induced by FeNTA in the kidney may contribute to the observed nephrotoxicity and carcinogenicity.
  • Published In

  • Carcinogenesis  Journal
  • Digital Object Identifier (doi)

    Author List

  • Athar M; Iqbal M
  • Start Page

  • 1133
  • End Page

  • 1139
  • Volume

  • 19
  • Issue

  • 6