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

  • Genotoxicity and Carcinogenicity
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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.

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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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Authors and Affiliations

  1. Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan

    Yasuaki Dewa, Jihei Nishimura, Masako Muguruma, Meilan Jin, Masaomi Kawai, Yukie Saegusa & Kunitoshi Mitsumori

  2. Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu, 501-1193, Japan

    Yasuaki Dewa, Jihei Nishimura, Masaomi Kawai, Yukie Saegusa & Toshiya Okamura

  3. Department of Applied Biological Science, United Graduate School of Agricultural Sciences, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan

    Meilan Jin

  4. Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Toshiya Okamura & Takashi Umemura

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  1. Yasuaki Dewa
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  2. Jihei Nishimura
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  9. Kunitoshi Mitsumori
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Correspondence to Yasuaki Dewa.

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Dewa, Y., Nishimura, J., Muguruma, M. et al. Involvement of oxidative stress in hepatocellular tumor-promoting activity of oxfendazole in rats. Arch Toxicol 83, 503–511 (2009). https://doi.org/10.1007/s00204-008-0349-z

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