Liver tumor promoting effect of omeprazole in rats and its possible mechanism of action.
Omeprazole (OPZ), a proton pump inhibitor, is a cytochrome P450 (CYP) 1A1/2 inducer. Some CYP1A inducers are known to have liver tumor promoting effects in rats and the ability to enhance oxidative stress. In this study, we performed a two-stage liver carcinogenesis bioassay in rats to examine the tumor promoting effect of OPZ (Experiment 1) and to clarify a possible mechanism of action (Experiment 2). In Experiment 1, male F344 rats were subjected to a two-third partial hepatectomy, and treated with 0, 138 or 276 mg/kg OPZ by oral gavage once a day for six weeks after an intraperitoneal injection of N-diethylnitrosamine (DEN). Liver weights significantly increased in the DEN+OPZ groups, and the number and area of glutathione S-transferase placental form (GST-P) positive foci significantly increased in the DEN+276 mg/kg OPZ group. In Experiment 2, the same experiment as Experiment 1 was performed, but the dosage of OPZ was 0 or 276 mg/kg. The number and area of GST-P positive foci as well as liver weights significantly increased in the DEN+276 mg/kg OPZ group. The number of proliferative cell nuclear antigen (PCNA)-positive cells also significantly increased in the same group. Real-time RT-PCR showed that the expression of AhR battery genes including Cyp1a1, Cyp1a2, Ugt1a6 and Nqo1, and Nrf2 battery genes including Gpx2, Yc2, Akr7a3, Aldh1a1 Me1 and Ggt1 were significantly upregulated in this group. However, the production of microsomal reactive oxygen species (ROS) and formation of thiobarbituric acid-reactive substances (TBARS) decreased, and 8-hydroxydeoxyguanosine (8-OHdG) content remained unchanged in this group. These results indicate that OPZ, CYP1A inducer, is a liver tumor promoter in rats, but oxidative stress is not involved in the liver tumor promoting effect of OPZ.
Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
Hitomi
H
Hayashi
Keisuke
K
Shimamoto
Eriko
E
Taniai
Yuji
Y
Ishii
Reiko
R
Morita
Kazuhiko
K
Suzuki
Makoto
M
Shibutani
Kunitoshi
K
Mitsumori
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000284:Administration, Oral; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2; D003580:Cytochromes / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D007274:Injections, Intraperitoneal / Q000379:methods; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone); D009853:Omeprazole / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D002273:Carcinogens; D003580:Cytochromes; D004052:Diethylnitrosamine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005979:Glutathione Peroxidase; C525844:glutathione peroxidase 2, rat; C017170:Cyp1a2 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D000080924:Aldehyde Dehydrogenase 1 Family; C523119:Aldh1a1 protein, rat; D050697:Retinal Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D014453:Glucuronosyltransferase; C107611:UDP-glucuronosyltransferase, UGT1A7; D005982:Glutathione Transferase; D003849:Deoxyguanosine; D009853:Omeprazole