title: 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.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Hojo
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiraki
authors.forename: Takuma
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D000090702:Constitutive Androstane Receptor; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004052:Diethylnitrosamine; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D011722:Pyrethrins / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D002273:Carcinogens; D000090702:Constitutive Androstane Receptor; D007306:Insecticides; D011722:Pyrethrins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D017392:Thiobarbituric Acid Reactive Substances; C076840:ethofenprox; D004052:Diethylnitrosamine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005982:Glutathione Transferase; D003849:Deoxyguanosine