Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Tokyo, Japan.
J Toxicol Sci. 2012;37(3):491-501. doi: 10.2131/jts.37.491.
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.
奥美拉唑（OPZ）是一种质子泵抑制剂，也是细胞色素 P450（CYP）1A1/2 诱导剂。一些 CYP1A 诱导剂已知在大鼠中具有肝肿瘤促进作用，并具有增强氧化应激的能力。在这项研究中，我们在大鼠中进行了两阶段肝致癌生物测定，以检查 OPZ 的肿瘤促进作用（实验 1）并阐明可能的作用机制（实验 2）。在实验 1 中，雄性 F344 大鼠接受三分之二部分肝切除术，并在腹腔内注射 N-二乙基亚硝胺（DEN）后每天通过口服灌胃给予 0、138 或 276mg/kg OPZ 一次，持续六周。 DEN+OPZ 组的肝重显著增加，DEN+276mg/kg OPZ 组的 GST-P 阳性灶的数量和面积显著增加。在实验 2 中，进行了与实验 1 相同的实验，但 OPZ 的剂量为 0 或 276mg/kg。 DEN+276mg/kg OPZ 组的 GST-P 阳性灶的数量和面积以及肝重均显著增加。增殖细胞核抗原（PCNA）阳性细胞的数量也显著增加。实时 RT-PCR 显示，该组 Cyp1a1、Cyp1a2、Ugt1a6 和 Nqo1 等 AhR 电池基因以及 Gpx2、Yc2、Akr7a3、Aldh1a1 Me1 和 Ggt1 等 Nrf2 电池基因的表达显著上调。然而，该组的微粒体反应性氧物种（ROS）的产生和硫代巴比妥酸反应物质（TBARS）的形成减少，8-羟基脱氧鸟苷（8-OHdG）含量保持不变。这些结果表明，作为 CYP1A 诱导剂的 OPZ 是大鼠的肝肿瘤促进剂，但氧化应激不参与 OPZ 的肝肿瘤促进作用。
