title: Enhanced liver tumor promotion but not liver initiation activity in rats subjected to combined administration of omeprazole and β-naphthoflavone.
abstract: Omeprazole (OPZ) and β-naphthoflavone (BNF) are cytochrome P450 (CYP)1A inducers and have liver tumor promoting effects. In this study, we investigated the co-promoting and co-initiating effects of OPZ and BNF in rats. In Experiment 1, male rats were subjected to partial hepatectomy (PH), and given oral doses of 138 or 276 mg/kg OPZ, 0.125% or 0.25% BNF or 138 mg/kg OPZ+0.125% BNF (n = 9~12) for 6 weeks after N-diethylnitrosamine (DEN) initiation. In Experiment 2, male rats were treated with oral doses of 138 or 276 mg/kg OPZ, 0.03% or 0.06% BNF or 138 mg/kg OPZ+0.03% BNF (n = 11~12) for 9 days starting 1 week before initiating treatment. As an initiating treatment, 2-Amino-3,4-dimethylimidazo[4,5-f]quinolone (MeIQx) was orally administered 12 hr after PH. The rats were fed a basal diet for 15 days, followed by a diet containing 0.015% 2-acetylaminofluorene for the next  10 days with a single oral dose of carbon tetrachloride. In Experiment 1, the number and area of glutathione S-transferase placental form-positive foci in the OPZ+BNF group were significantly higher than the average values of the High OPZ or the High BNF group. The expression of cyclooxygenase-2 (Cox-2) and COX-2 protein in the liver significantly increased in the OPZ+BNF group. In Experiment 2, liver initiation activity was not enhanced by the co-administration of OPZ+BNF. The results of our studies suggest that the co-administration of OPZ and BNF results in synergistic effects in the liver tumor promotion probably owing to increased COX-2 expression, but no modifying effect in the liver initiation activity of MeIQx in rats.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan. hayashih@cc.tuat.ac.jp
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Eriko
authors.initials: E
authors.lastname: Taniai
authors.forename: Reiko
authors.initials: R
authors.lastname: Morita
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hayashi
authors.forename: Daichi
authors.initials: D
authors.lastname: Nakamura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Wakita
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; D002251:Carbon Tetrachloride; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004052:Diethylnitrosamine; D004357:Drug Synergism; D015227:Lipid Peroxidation / Q000187:drug effects; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009853:Omeprazole / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D011810:Quinoxalines; D051381:Rats; D011916:Rats, Inbred F344; D019324:beta-Naphthoflavone / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*
chemical_list: D002273:Carcinogens; D054328:Proton Pump Inhibitors; D011810:Quinoxalines; D004052:Diethylnitrosamine; D019324:beta-Naphthoflavone; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D002251:Carbon Tetrachloride; D019363:Cytochrome P-450 CYP1A1; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D009853:Omeprazole