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

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 Prkcα, 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.

• Authors: Mohammad Monir Tawfeeq, Hitomi Hayashi, Keisuke Shimamoto, Kazuhiko Suzuki, Makoto Shibutani, Hisashi Inokuma, Kunitoshi Mitsumori
• Journal: Archives of toxicology (Arch Toxicol) Vol. 86 Issue 3 Pg. 497-507 (Mar 2012) ISSN: 1432-0738 [Electronic] Germany
• PMID: 22076107 (Publication Type: Journal Article)

Chemical References

• Androgen Antagonists
• Reactive Oxygen Species
• Diethylnitrosamine
• Flutamide

Topics

• Androgen Antagonists (toxicity)
• Animals
• Body Weight (drug effects)
• Diethylnitrosamine
• Flutamide (toxicity)
• Immunohistochemistry
• Lipid Peroxidation (drug effects)
• Liver Neoplasms, Experimental (chemically induced, metabolism, pathology)
• MAP Kinase Signaling System
• Male
• Organ Size (drug effects)
• Rats
• Rats, Inbred F344
• Reactive Oxygen Species (metabolism)