Liver tumor promoting effect of etofenprox in rats and its possible mechanism of action.

Abstract

To investigate the liver tumor-promoting effects of etofenprox (ETF), a pyrethroid-like insecticide, 6 week-old male F344 rats were given an intraperitoneal injection of N-diethylnitrosamine (DEN). After 2 weeks from the DEN treatment, 12 rats per group received a powdered diet containing 0, 0.25, 0.50, or 1.0% ETF for 8 weeks. At the time of 2nd week of ETF administration, all animals were subjected to two-thirds partial hepatectomy (PH). One rat per group except for the 0.25% ETF group died due to surgical operation of PH. The number and area of glutathione S-transferase placental form (GST-P) positive foci significantly increased in the livers of DEN-initiated rats given 0.50% and 1.0% ETF compared with the DEN-alone group. Quantitative real-time RT-PCR analysis revealed that the mRNA expression of phase I enzymes Cyp2b1/2, phase II enzymes such as Akr7a3, Gsta5, Ugt1a6, Nqo1 significantly increased in the DEN+ETF groups. The immunohistochemistry showed the translocation of CAR from the cytoplasm to the nuclei of hepatocytes in the ETF-treated groups. Reactive oxygen species (ROS) production increased in microsomes isolated from the livers of ETF-treated rats, and thiobarbituric acid-reactive substances (TBARS) levels and 8- hydroxy-2-deoxyguanosine (8-OHdG) content significantly increased in all of the ETF-treated groups and DEN+1.0% ETF group, respectively. The results of the present study indicate that ETF has a liver tumor-promoting activity in rats, and suggest that ETF activates the constitutive active/androstane receptor (CAR) and enhances microsomal ROS production, resulting in the upregulation of Nrf2 gene batteries; such an oxidative stress subsequently induces liver tumor-promoting effects by increased cellular proliferation.

• Authors: Yuri Hojo, Ayako Shiraki, Takuma Tsuchiya, Keisuke Shimamoto, Yuji Ishii, Kazuhiko Suzuki, Makoto Shibutani, Kunitoshi Mitsumori
• Journal: The Journal of toxicological sciences (J Toxicol Sci) Vol. 37 Issue 2 Pg. 297-306 ( 2012) ISSN: 1880-3989 [Electronic] Japan
• PMID: 22467020 (Publication Type: Journal Article)

Chemical References

• Carcinogens
• Constitutive Androstane Receptor
• Insecticides
• Pyrethrins
• RNA, Messenger
• Reactive Oxygen Species
• Receptors, Cytoplasmic and Nuclear
• Thiobarbituric Acid Reactive Substances
• ethofenprox
• Diethylnitrosamine
• 8-Hydroxy-2'-Deoxyguanosine
• Glutathione Transferase
• Deoxyguanosine

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Animals
• Carcinogens (toxicity)
• Constitutive Androstane Receptor
• Deoxyguanosine (analogs & derivatives, metabolism)
• Diethylnitrosamine
• Gene Expression (drug effects)
• Glutathione Transferase (metabolism)
• Insecticides (toxicity)
• Liver Neoplasms, Experimental (chemically induced, metabolism, pathology)
• Male
• Microsomes, Liver (drug effects, metabolism)
• Pyrethrins (toxicity)
• RNA, Messenger (metabolism)
• Rats
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Thiobarbituric Acid Reactive Substances (metabolism)