Journal Article

Nordihydroguairetic acid is a potent inhibitor of ferric-nitrilotriacetate-mediated hepatic and renal toxicity, and renal tumour promotion, in mice

Sabah Ansar, Mohammad Iqbal and Mohammad Athar

in Carcinogenesis

Volume 20, issue 4, pages 599-606
Published in print April 1999 | ISSN: 0143-3334
Published online April 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.4.599
Nordihydroguairetic acid is a potent inhibitor of ferric-nitrilotriacetate-mediated hepatic and renal toxicity, and renal tumour promotion, in mice

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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.

Keywords: CDNB, 1-chloro-2,4-dinitrobenzene; DEN, N-diethylnitrosamine; DTNB, 5,5′-dithio-bis-2-nitrobenzoic acid; Fe-NTA, ferric-nitrilotriacetate; GSH, glutathione; NDGA, nordihydroguairetic acid; ODC, ornithine decarboxylase; 8-OH-dG, 8-hydroxy deoxyguanosine; PCA, perchloric acid; PMS, post-mitochondrial supernatant; PMSF, phenylmethylsulphonyl fluoride; RCT, renal cell tumour; ROS, reactive oxygen species; TBA, thiobarbituric acid; TCA, trichloroacetic acid.

Journal Article.  6468 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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