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Archives of Toxicology

, Volume 83, Issue 5, pp 503–511 | Cite as

Involvement of oxidative stress in hepatocellular tumor-promoting activity of oxfendazole in rats

  • Yasuaki DewaEmail author
  • Jihei Nishimura
  • Masako Muguruma
  • Meilan Jin
  • Masaomi Kawai
  • Yukie Saegusa
  • Toshiya Okamura
  • Takashi Umemura
  • Kunitoshi Mitsumori
Genotoxicity and Carcinogenicity

Abstract

The tumor-promoting effects of oxfendazole (OX), a benzimidazole anthelmintic, were investigated using a medium-term rat hepatocarcinogenesis model. Six-week-old male F344 rats received an intraperitoneal injection of N-diethylnitrosamine (DEN) and were given a powdered diet containing 0 or 500 ppm OX for 6 weeks from 2 weeks after DEN treatment. All animals were subjected to two-thirds partial hepatectomy 1 week after OX treatment. The numbers and areas of glutathione S-transferase placental form (GST-P)-positive foci were significantly increased in the livers of rats treated with OX, with concomitantly increased cell proliferation, compared with those in the livers of the DEN alone group. Quantitative real-time RT-PCR analysis revealed that OX induced not only mRNA expression of phase I enzymes Cyp1a1, Cyp1a2, but also Nrf2-regulated phase II enzymes such as Gpx2, Nqo1, Yc2, Akr7a3 and Gstm1, presumably due to an adaptive response against OX-induced oxidative stress. Reactive oxygen species production increased in microsomes isolated from the livers of OX-treated rats. Furthermore, OX enhanced oxidative DNA damage (as assessed by 8-hydroxydeoxyguanosine; 8-OHdG) and lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; TBARS). These results suggest that administration of OX at a high dose and for a long term enhances oxidative stress responses, which may contribute to its tumor-promoting potential in rats.

Keywords

Oxfendazole Reactive oxygen species Oxidative stress Tumor-promotion Rat 

Notes

Acknowledgments

This research was partly supported by a grant-in-aid for research on the safety of veterinary drug residues in food of animal origin from the Ministry of Health, Labor and Welfare of Japan (H19-shokuhin-ippan-011).

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Yasuaki Dewa
    • 1
    • 2
    Email author
  • Jihei Nishimura
    • 1
    • 2
  • Masako Muguruma
    • 1
  • Meilan Jin
    • 1
    • 3
  • Masaomi Kawai
    • 1
    • 2
  • Yukie Saegusa
    • 1
    • 2
  • Toshiya Okamura
    • 2
    • 4
  • Takashi Umemura
    • 4
  • Kunitoshi Mitsumori
    • 1
  1. 1.Laboratory of Veterinary PathologyTokyo University of Agriculture and TechnologyFuchu-shi, TokyoJapan
  2. 2.Pathogenetic Veterinary Science, United Graduate School of Veterinary SciencesGifu UniversityGifu-shi, GifuJapan
  3. 3.Department of Applied Biological Science, United Graduate School of Agricultural SciencesTokyo University of Agriculture and TechnologyFuchu-shi, TokyoJapan
  4. 4.Division of PathologyNational Institute of Health SciencesSetagaya-ku, TokyoJapan

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