title: Suppressive effect of liver tumor-promoting activities in rats subjected to combined administration of phenobarbital and piperonyl butoxide.
abstract: Phenobarbital (PB) is a cytochrome P450 (CYP) 2B inducer, and piperonyl butoxide (PBO) is a CYP1A/2B inducer. These inducers have liver tumor-promoting effects in rats. In this study, we performed a rat two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of PB and PBO co-administration. Male rats received an intraperitoneal injection of N-diethylnitrosamine (DEN) for initiation. Two weeks after DEN administration, rats were given PB (60 or 120 ppm in drinking water), PBO (1,250 or 2,500 ppm in diet) or 60 ppm PB+1,250 ppm PBO for 6 weeks. One week after the PB/PBO treatment, all rats were subjected to a two-thirds partial hepatectomy. To evaluate the effect of the combined administration, we used two statistical additive models. In the isoadditive model, the average values of the area of GST-P positive foci in the PB+PBO group were significantly lower than those in the High PB or High PBO groups. In the heteroadditive model, the net values of Cyp1a1 mRNA level and microsomal reactive oxygen species (ROS) production in the PB+PBO group were significantly lower than the sum of those in the Low PB or Low PBO groups. On the contrary, there was no interactive effect in the PCNA-positive hepatocyte ratio, mRNA levels of Cyp2b1/2, Gstm3, Gpx2 and Nqo1, and the level of thiobarbituric acid-reactive substances in the PB+PBO group. These results suggest that PB and PBO co-administration causes suppressive effects in liver tumor-promoting activity in rats resulting from inhibited microsomal ROS production because of suppression of CYP1A induction.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology.
authors.forename: Reiko
authors.initials: R
authors.lastname: Morita
authors.forename: Atsunori
authors.initials: A
authors.lastname: Yafune
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiraki
authors.forename: Megu
authors.initials: M
authors.lastname: Itahashi
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Akane
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Nakane
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: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D003864:Depression, Chemical; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004790:Enzyme Induction / Q000187:drug effects; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010634:Phenobarbital / Q000008:administration & dosage* / Q000494:pharmacology; D010882:Piperonyl Butoxide / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D004052:Diethylnitrosamine; D019363:Cytochrome P-450 CYP1A1; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat; D010882:Piperonyl Butoxide; D010634:Phenobarbital