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Antioxidant enzymatically modified isoquercitrin or melatonin supplementation reduces oxidative stress-mediated hepatocellular tumor promotion of oxfendazole in rats

  • Genotoxicity and Carcinogenicity
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Abstract

To clarify whether enzymatically modified isoquercitrin (EMIQ) or melatonin (MLT) supplementation reduces oxidative stress-mediated hepatocellular tumor-promoting effect of oxfendazole (OX), a benzimidazole anthelmintic, male rats were administered a single intraperitoneal injection of N-diethylnitrosamine (DEN) and were fed a diet containing OX (500 ppm) for 10 weeks with or without EMIQ (2,000 ppm) or MLT (100 ppm) in the drinking water after DEN initiation. One week after the commencement of the administration of OX, rats were subjected to two-thirds of partial hepatectomy. The number of GST-P-positive foci promoted by OX was significantly inhibited by the combined antioxidant EMIQ or MLT administration, and the area of GST-P-positive foci was inhibited by the administration of MLT. Real-time RT–PCR analysis revealed decreases in mRNA expression levels of cytochrome P450, family 2, subfamily b, polypeptide 2 (Cyp2b2) and malic enzyme 1 (Me1) in the DEN-OX-EMIQ and DEN-OX-MLT groups and decreases in mRNA expression levels of Cyp1a1 and aldo–keto reductase family 7, member A3 (Akr7a3) in the DEN-OX-MLT group compared to those in the DEN-OX group. In in vitro ROS production assay, inhibited production of NADPH-dependent ROS was observed by the treatment with EMIQ or MLT. These results suggest that coadministration of EMIQ or MLT suppresses the hepatocellular tumor-promoting activity of OX in rats through the decrease in ROS production by the activation of CYPs.

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Abbreviations

OX:

Oxfendazole

EMIQ:

Enzymatically modified isoquercitrin

MLT:

Melatonin

AhR:

Aryl hydrocarbon receptor

DEN:

N-diethylnitrosamine

GST-P:

Glutathione S-transferase placental form

Real-time RT–PCR:

Quantitative real-time reverse transcription-polymerase chain reaction

Nrf2:

NF-E2-related factor 2

ROS:

Reactive oxygen species

H2DCFDA:

2′,7′-Dichlorodihydrofluorescein diacetate

DCF:

2′,7′-Dichlorofluorescein

NADPH:

Nicotinamide adenine dinucleotide phosphate

Cyp1a1:

Cytochrome P450, family 1, subfamily a, polypeptide 1

Cyp1a2:

Cytochrome P450, family 1, subfamily a, polypeptide 2

Cyp2b2:

Cytochrome P450, family 2, subfamily b, polypeptide 2

Nqo1:

NAD(P)H dehydrogenase, quinone 1

Gstm1:

Glutathione S-transferase, mu 1

Gpx2:

Glutathione peroxidase 2

Akr7a3:

Aldo–keto reductase family 7, member A3

Yc2:

Glutathione S-transferase Yc2 subunit

Me1:

Malic enzyme 1

AFAR:

Aflatoxin B1 aldehyde reductase

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Acknowledgments

This study was supported in part by a grant from the Ministry of Health, Labor and Welfare of Japan and San-Ei Gen F.F.I, Inc. (Osaka, Japan).

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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

    Jihei Nishimura, Yukie Saegusa, Yasuaki Dewa, Meilan Jin, Masaomi Kawai, Sayaka Kemmochi, Tomoaki Harada, Makoto Shibutani & Kunitoshi Mitsumori

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

    Jihei Nishimura, Yukie Saegusa, Yasuaki Dewa, Masaomi Kawai & Sayaka Kemmochi

  3. Biochemistry and Biotechnology, 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. San-Ei Gen F.F.I, Inc., 1-1-11, Sanwa-cho, Toyonaka-shi, Osaka, 561-8588, Japan

    Shim-mo Hayashi

Authors
  1. Jihei Nishimura
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  2. Yukie Saegusa
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  3. Yasuaki Dewa
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  4. Meilan Jin
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  5. Masaomi Kawai
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  10. Kunitoshi Mitsumori
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Correspondence to Kunitoshi Mitsumori.

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Nishimura, J., Saegusa, Y., Dewa, Y. et al. Antioxidant enzymatically modified isoquercitrin or melatonin supplementation reduces oxidative stress-mediated hepatocellular tumor promotion of oxfendazole in rats. Arch Toxicol 84, 143–153 (2010). https://doi.org/10.1007/s00204-009-0497-9

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