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Gene expression analyses of the liver in rats treated with oxfendazole

  • Organ Toxicity and Mechanisms
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Abstract

The effect of oxfendazole (OX), a benzimidazole anthelmintic, on hepatic gene expression was investigated in the liver of rats as a preliminary study to elucidate the possible mechanism of its non-genotoxic hepatocarcinogenesis. The liver from a male F344/N rat given a diet containing 500 ppm of OX for 3 weeks was examined by global gene expression analysis in comparison with an untreated rat. Microarray analysis revealed that phase I and phase II detoxifying enzymes were up-regulated in an OX-treated rat. In addition to these genes, the expressions of several upregulated genes related to xenobiotic metabolism and oxidative stress [e.g. Cyp1a1; NAD(P)H dehydrogenase, quinone 1 (Nqo1); glutathione peroxidase 2 (Gpx2); glutathione S-transferase Yc2 subunit (Yc2)], were confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR). Furthermore, rats were administered 500 or 1,000 ppm of OX for 9 weeks, and the effect of OX on oxidative stress responses was evaluated by real-time RT-PCR along with conventional toxicological assays, including lipid peroxidation (thiobarbituric acid-reactive substance; TBARS). A longer treatment period and/or a higher dose of OX tended to increase the gene expressions of not only phase I (Cyp1a1 and Cyp1a2) but also phase II (Nqo1, Gpx2, Yc2, and Akr7a3) drug metabolizing enzymes. Toxicological parameters, such as TBARS, serum aspartate aminotransferase (AST), and serum alkaline phosphatase (ALP), showed slight but significant increases after treatment with OX for 9 weeks. These results indicate that OX elicits adaptive responses against oxidative stress in the liver and suggest that the imbalance in redox status might be one of the factors triggering the initial step of OX-induced non-genotoxic carcinogenesis in the liver of rats.

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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, Sayaka Matsumoto, Meilan Jin & 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

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

    Miwa Takahashi

  4. 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

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  1. Yasuaki Dewa
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  2. Jihei Nishimura
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  3. Masako Muguruma
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  4. Sayaka Matsumoto
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  5. Miwa Takahashi
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  7. Kunitoshi Mitsumori
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Correspondence to Yasuaki Dewa.

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Dewa, Y., Nishimura, J., Muguruma, M. et al. Gene expression analyses of the liver in rats treated with oxfendazole. Arch Toxicol 81, 647–654 (2007). https://doi.org/10.1007/s00204-007-0190-9

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  • DOI: https://doi.org/10.1007/s00204-007-0190-9

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