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Immunohistochemical analyses at the late stage of tumor promotion by oxfendazole in a rat hepatocarcinogenesis model

  • Genotoxicity and Carcinogenicity
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Abstract

The present study was performed to characterize immunohistochemically the expression levels of molecules related to not only xenobiotic and antioxidant functions but also cell proliferation and apoptosis in neoplastic lesions induced by the benzimidazole anthelmintic, oxfendazole (OX), at the late stage of its tumor promotion in a rat hepatocarcinogenesis model. Male F344 rats were initiated with an intraperitoneal injection of 200 mg/kg N-diethylnitrosamine, and 2 weeks later they were fed a diet containing 0% (basal diet) or 0.05% OX for 26 weeks. All animals were subjected to a two-thirds partial hepatectomy at week 3 and killed at week 28. Histopathologically, OX increased the incidence and multiplicity of altered foci (4.0- and 3.6-fold, respectively) and hepatocellular adenomas (HCAs) (3.0- and 5.5-fold, respectively). OX treatment induced 5.2- and 5.6-fold increases in the number of proliferating cell nuclear antigen (PCNA)-positive cells and single-stranded DNA (ssDNA)-positive cells in HCAs compared with the surrounding tissue, respectively. Staining for the cell cycle regulators P21 and C/EBPα and the AhR-regulated CYP1A1 molecules decreased but increased reactivity of the Nrf2-regulated, detoxifing/antioxidant molecules aldo–keto reductase 7 (AKR7) and glutathione peroxidase 2 (GPX2) were also seen in HCAs compared with the surrounding hepatocytes. These results suggest that dysregulation of cell proliferation and apoptosis and escape from oxidative stress elicited by OX treatment play an important role in OX-induced hepatocarcinogenesis 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, Labour 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, Meilan Jin, Masaomi Kawai, Yukie Saegusa, Sayaka Kenmochi, Keisuke Shimamoto, Tomoaki Harada, Makoto Shibutani & Kunitoshi Mitsumori

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

    Yasuaki Dewa, Jihei Nishimura, Masaomi Kawai, Yukie Saegusa, Sayaka Kenmochi & Keisuke Shimamoto

  3. Division of Pathology, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Meilan Jin

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  1. Yasuaki Dewa
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  2. Jihei Nishimura
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  4. Masaomi Kawai
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  9. Makoto Shibutani
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  10. Kunitoshi Mitsumori
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Correspondence to Kunitoshi Mitsumori.

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Dewa, Y., Nishimura, J., Jin, M. et al. Immunohistochemical analyses at the late stage of tumor promotion by oxfendazole in a rat hepatocarcinogenesis model. Arch Toxicol 85, 155–162 (2011). https://doi.org/10.1007/s00204-010-0557-1

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  • DOI: https://doi.org/10.1007/s00204-010-0557-1

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