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Possible involvement of oxidative stress in fenofibrate-induced hepatocarcinogenesis in rats

  • Genotoxicity and Carcinogenicity
  • Published:
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Abstract

To clarify whether oxidative stress is involved in the development of hepatocellular preneoplastic foci induced by fenofibrate (FF), a peroxisome proliferator-activated receptor alpha agonist, male F344/N rats were fed a diet containing 6,000, 3,000, or 0 ppm of FF for 13 weeks after N-diethylnitrosamine initiation. Two-third partial hepatectomy was performed 1 week after the FF treatment. Histopathologically, the number of hepatocellular altered foci significantly increased in the FF-treated groups with a concomitant increase in the number of hepatocytes positive for anti-Ki-67 antibody, but the number and area of glutathione S-transferase placental form (GST-P)-positive foci decreased in these groups, as compared to those in the controls. Microarray analysis or quantitative real-time reverse transcription-polymerase chine reaction demonstrated the significant up-regulations of Aco and Cyp4a1 (genes related to lipid metabolism); Gpx2, Yc2, Cat, Cyp2b15, and Ugt1a6 (metabolic oxidative stress-related genes); Apex1, Mgmt, Xrcc5, Nbn, and Gadd45a (DNA repair-related genes); and Ccnd1 (cell cycle-related genes) in the FF-treated groups, and the significant down-regulations of Cyp1a2, Gsta2, Gstm2, and Gstm3 (phase I or II metabolism-related genes); Mlh1 and Top1 (DNA repair-related genes); and Cdkn1a, Cdkn1b, Chek2, and Gadd45b (cell cycle/apoptosis-related genes) in these rats. FF-treatment increased the activity of enzymes such as carnitine acetyltransferase, carnitine palmitoyltransferase, fatty acyl-CoA oxidizing system, and catalase in the liver, but not superoxide dismutase in the liver. In addition, 8-OHdG level in liver DNA, lipofuscin deposition in hepatocytes, and in vitro reactive oxygen species production in microsomes significantly increased due to FF treatment. These results suggest that oxidative stress is involved in the development of FF-induced hepatocellular preneoplastic foci in rats.

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Abbreviations

FF:

Fenofibrate

DEN:

N-diethylnitrosamine

PPARα:

Peroxisome proliferator-activated receptor-alpha

H2O2 :

Hydrogen peroxide

H&E:

Hematoxylin and eosin

GST-P:

Glutathione S-transferase placental form

HAF:

Hepatocellular altered foci

ROS:

Reactive oxygen species

8-OHdG:

8-Hydroxydeoxyguanosine

DCFH-DA:

2′, 7′-Dichlorodihydrofluorescein diacetate

RT-PCR:

Reverse transcription-polymerase chine reaction

CAT:

Carnitine acetyltransferase

CPT:

Carnitine palmitoyltransferase

FAOS:

Fatty acyl-CoA oxidizing system

DTNB:

5,5′-Dithio-bis-(2-nitrobenzoic acid)

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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, Yasuaki Dewa, Masako Muguruma, Meilan Jin, 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

    Jihei Nishimura, Yasuaki Dewa, Toshiya Okamura & Yukie Saegusa

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

    Toshiya Okamura & Takashi Umemura

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  1. Jihei Nishimura
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  2. Yasuaki Dewa
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  3. Toshiya Okamura
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Correspondence to Jihei Nishimura.

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Nishimura, J., Dewa, Y., Okamura, T. et al. Possible involvement of oxidative stress in fenofibrate-induced hepatocarcinogenesis in rats. Arch Toxicol 82, 641–654 (2008). https://doi.org/10.1007/s00204-007-0278-2

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  • DOI: https://doi.org/10.1007/s00204-007-0278-2

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