title: Nordihydroguairetic acid is a potent inhibitor of ferric-nitrilotriacetate-mediated hepatic and renal toxicity, and renal tumour promotion, in mice.
abstract: Ferric-nitrilotriacetate (Fe-NTA) is a known renal carcinogen. In the present study, we report the effect of a potent lignin-derived herbal antioxidant, nordihydroguairetic acid (NDGA), against Fe-NTA-mediated tissue toxicity. Fe-NTA (alone) treatment of mice enhances ornithine decarboxylase activity to 259% in liver and 341% in kidney and increases [3H]thymidine incorporation in DNA to 250% in liver and 324% in kidney compared with the corresponding saline-treated controls. The enhanced ornithine decarboxylase activity and DNA synthesis showed a reduction to 138 and 123%, respectively, in liver at a higher dose of 2 mg NDGA/day/animal whereas in kidney the reduction was to 118 and 102%, respectively, compared with the corresponding saline-treated controls. In the Fe-NTA (alone)-treated group, a 12% renal tumour incidence was recorded whereas, in N-diethylnitrosamine (DEN)-initiated and Fe-NTA-promoted animals, the percentage tumour incidence was increased to 68% as compared with untreated controls. No tumour incidence was recorded in the DEN-initiated, non-promoted group. The administration of NDGA, afforded >80% protection against DEN- and Fe-NTA-mediated renal tissue injury in vivo. Fe-NTA treatment also enhanced hepatic and renal microsomal lipid peroxidation to 170 and 205% of saline-treated controls, respectively, and hydrogen peroxide generation by >2.5-fold in both tissues accompanied by a 51 and 21% decrease in the level of glutathione and 35-48 and 35-50% decrease in the activities of glutathione-metabolizing and antioxidant enzymes in liver and kidney, respectively. These changes were reversed significantly in animals receiving a pre-treatment of NDGA. Our data show that NDGA can abrogate the toxic and tumour-promoting effects of Fe-NTA in liver and kidney of mice and can serve as a potent chemopreventive agent to suppress oxidant-induced tissue injury and tumorigenesis.
authors.affiliation: Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Ansar
authors.forename: M
authors.initials: M
authors.lastname: Iqbal
authors.forename: M
authors.initials: M
authors.lastname: Athar
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001806:Blood Urea Nitrogen; D002273:Carcinogens / Q000037:antagonists & inhibitors / Q000633:toxicity; D002374:Catalase / Q000378:metabolism; D003404:Creatinine / Q000032:analysis; D004261:DNA Replication / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity; D005290:Ferric Compounds / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000032:analysis; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009637:Masoprocol / Q000494:pharmacology*; D051379:Mice; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; D002273:Carcinogens; D005290:Ferric Compounds; D004052:Diethylnitrosamine; D009637:Masoprocol; D003404:Creatinine; D006861:Hydrogen Peroxide; D005954:Glucosephosphate Dehydrogenase; D002374:Catalase; D005980:Glutathione Reductase; D005723:gamma-Glutamyltransferase; D005982:Glutathione Transferase; D009955:Ornithine Decarboxylase; D005978:Glutathione; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate