Renal carcinogenesis induced by ferric nitrilotriacetate in mice, and protection from it by Brazilian propolis and artepillin C

Pathol Int. 2000 Sep;50(9):679-89. doi: 10.1046/j.1440-1827.2000.01097.x.


The protective effect of Brazilian propolis and its extract Artepillin C against ferric nitrilotriacetate (Fe-NTA)-induced renal lipid peroxidation and carcinogenesis was studied in male ddY mice. Fe-NTA-induced renal lipid peroxidation leads to a high incidence of renal cell carcinoma (RCC) in mice. Administration of propolis by gastric intubation 2 h before or Artepillin C at either the same time, 2 h, or 5 h before the intraperitoneal injection of Fe-NTA (7 mg Fe/kg) effectively inhibited renal lipid peroxidation. This was evaluated from the measurement of renal thiobarbituric acid-reactive substances (TBARS) or histochemical findings of 4-hydroxy-2-nonenal (4-HNE)-modified proteins and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Repeated injection of Fe-NTA (10 mg Fe/kg per day, twice a week for a total of 16 times in 8 weeks) caused subacute nephrotoxicity as revealed by necrosis and pleomorphic large nuclear cells in the renal proximal tubules, and gave rise to RCC 12 months later. A protective effect from carcinogenicity was observed in mice given propolis or Artepillin C. Furthermore, the mice given Fe-NTA only developed multiple cysts composed of precancerous lesions with multilayered and proliferating large atypical cells. Mice treated with propolis and Artepillin C also had cysts, but these were dilated and composed of flat cells. These results suggest that propolis and Artepillin C prevent oxidative renal damage and the carcinogenesis induced by Fe-NTA in mice.

MeSH terms

  • 8-Hydroxy-2'-Deoxyguanosine
  • Aldehydes / metabolism
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Renal Cell / chemically induced
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / prevention & control
  • Deoxyguanosine / analogs & derivatives*
  • Deoxyguanosine / metabolism
  • Disease Models, Animal
  • Electron Spin Resonance Spectroscopy
  • Female
  • Ferric Compounds / toxicity
  • Fluorescent Antibody Technique, Indirect
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Neoplasms / chemically induced
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / prevention & control
  • Lipid Peroxidation / drug effects
  • Male
  • Mice
  • Mutagens / toxicity
  • Nitrilotriacetic Acid / analogs & derivatives*
  • Nitrilotriacetic Acid / toxicity
  • Phenylpropionates / administration & dosage
  • Phenylpropionates / pharmacokinetics
  • Phenylpropionates / therapeutic use*
  • Propolis / administration & dosage
  • Propolis / therapeutic use*
  • Thiobarbituric Acid Reactive Substances / metabolism


  • Aldehydes
  • Antineoplastic Agents
  • Ferric Compounds
  • Mutagens
  • Phenylpropionates
  • Thiobarbituric Acid Reactive Substances
  • artepillin C
  • 8-Hydroxy-2'-Deoxyguanosine
  • Propolis
  • Deoxyguanosine
  • 4-hydroxy-2-nonenal
  • Nitrilotriacetic Acid
  • ferric nitrilotriacetate