Mechanistic study on liver tumor promoting effects of flutamide in rats.

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  • Additional Information
    • Source:
      Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 0417615 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-0738 (Electronic) Linking ISSN: 03405761 NLM ISO Abbreviation: Arch Toxicol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Berlin, New York, Springer-Verlag.
    • Subject Terms:
      Androgen Antagonists/*toxicity ; Flutamide/*toxicity ; Liver Neoplasms, Experimental/*chemically induced; Animals ; Body Weight/drug effects ; Diethylnitrosamine ; Immunohistochemistry ; Lipid Peroxidation/drug effects ; Liver Neoplasms, Experimental/metabolism ; Liver Neoplasms, Experimental/pathology ; MAP Kinase Signaling System ; Male ; Organ Size/drug effects ; Rats ; Rats, Inbred F344 ; Reactive Oxygen Species/metabolism
    • Abstract:
      Flutamide (FLU), a nonsteroidal anti-androgen, is used for the treatment of prostate cancer but is also a cytochrome P450 (CYP) 1A inducer. Some CYP1A inducers are known to exert hepatocellular tumor-promoting activities in rodents, and reactive oxygen species (ROS) produced by CYP1A1 induction via a metabolism of FLU is probably involved in the liver tumor promotion. In the present study, to clarify the possible liver tumor promoting effect of FLU, a two-stage liver carcinogenesis assay was performed using male F344 rats. Rats received an intraperitoneal (ip) injection of 200 mg/kg body weight of N-diethylnitrosamine (DEN) and fed a diet containing 0, 0.1 or 0.2% FLU for 6 weeks. After 2 weeks of DEN treatment, all rats were subjected to two-thirds partial hepatectomy. Animals were killed 8 weeks after ip injection of DEN. Immunohistochemically, the number and area of glutathione S-transferase placental form (GST-P)-positive foci significantly increased in the liver of rats given 0.2% FLU as compared with the control. Ki-67-positive cell ratio also increased in rats given FLU at both concentrations. ROS generation in the microsomal fraction and production of thiobarbituric acid-reactive substance [TBARS] and 8-hydroxy-2'-deoxyguanosine (8-OHdG) content in the liver did not increase in any of the FLU-treated groups. The results of microarray and real-time RT-PCR revealed that phase 1 drug-metabolizing enzymes such as CYP1A1, Ugt1a61 and Nqo1 and phase II drug-metabolizing enzymes such as Yc2, Akr1b7, Akr1b8, Akr1b10, Aldh1a1, Gpx2 and Me1 were up-regulated in rats treated with FLU. In addition, the MAPK pathway family-related genes such as PrkcĪ±, Mek1, Rafb, Myc, Mek2, Raf1 and Egfr were also up-regulated in FLU-treated groups. The results of the present study indicate that FLU is a CYP1A inducer but does not cause any production of microsomal ROS in the liver and suggest that microsomal ROS is not involved in the liver tumor promoting effect of FLU.
    • Accession Number:
      0 (Androgen Antagonists)
      0 (Reactive Oxygen Species)
      3IQ78TTX1A (Diethylnitrosamine)
      76W6J0943E (Flutamide)
    • Publication Date:
      Date Created: 20111115 Date Completed: 20120717 Latest Revision: 20131121
    • Publication Date:
      20221213
    • Accession Number:
      10.1007/s00204-011-0776-0
    • Accession Number:
      22076107