FERRIC NITRILOTRIACETATE PROMOTES N-DIETHYLNITROSAMINE-INDUCED RENAL TUMORIGENESIS IN THE RAT - IMPLICATIONS FOR THE INVOLVEMENT OF OXIDATIVE STRESS

Ferric nitrilotriacetate (Fe-NTA) is a known complete renal carcinogen . In this study we show that Fe-NTA is a potent inducer of renal ornit hine decarboxylase (ODC) activity and DNA synthesis and promoter of N- diethylnitrosamine (DEN)-induced renal tumorigenesis in rat. Fe-NTA in duced renal ODC activity several fold as compared with saline-treated rats. Renal DNA synthesis, measured as [H-3]thymidine incorporation in to DNA, was increased after Fe-NTA treatment, Similar to other known t umor promoters, Fe-NTA also depleted the antioxidant armory of the tis sue, It depleted glutathione (GSH) levels to similar to 55 % of saline -treated controls. It also led to a dose-dependent decrease in the act ivities of glutathione reductase and glutathione S-transferase, Simila rly, activities of catalase, glutathione peroxidase and glucose 6-phos phate dehydrogenase decreased significantly (45-65%), In contrast, gam ma-glutamyl transpeptidase activity showed an increase. The maximum ch anges in activities of these enzymes could be observed at 12 h followi ng Fe-NTA treatment. In addition, Fe-NTA augmented renal microsomal li pid peroxidation >150% over saline-treated controls, which was concomi tant with the alterations in GSH metabolizing enzymes and depletion of the antioxidant armory. These effects were alleviated in rats which r eceived a pretreatment,vith an antioxidant, BHA or BHT. Fe-NTA promote d DEN-induced renal tumorigenesis, In saline alone- and DEN alone-trea ted animals no tumors could be recorded, whereas in Fe-NTA alone-treat ed animals 17% tumor incidence was observed, However, in DEN-initiated and Fe-NTA-promoted animals tumor incidence increased to 71%. Our res ults show that Fe-NTA induces oxidative stress in the kidney and decre ases antioxidant defenses, as indicated by the fall in GSH level and i n the activities of glutathione peroxidase and catalase, Concomitantly , Fe-NTA increases ODC activity and DNA synthesis, which may be compen satory changes following oxidative injury to renal cells in addition t o providing a strong stimulus for renal tumor promotion. Thus oxidativ e stress and impaired antioxidant defenses induced by Fe-NTA in the ki dney may contribute to the observed nephrotoxicity and carcinogenicity .