Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
J Toxicol Sci. 2012;37(5):969-85. doi: 10.2131/jts.37.969.
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 = 912) 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 = 1112) 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.
奥美拉唑（OPZ）和β-萘黄酮（BNF）是细胞色素 P450（CYP）1A 的诱导剂，具有肝肿瘤促进作用。在这项研究中，我们研究了 OPZ 和 BNF 在大鼠中的协同促进和协同引发作用。在实验 1 中，雄性大鼠接受部分肝切除术（PH），并在 N-二乙基亚硝胺（DEN）起始后给予口服剂量为 138 或 276mg/kg OPZ、0.125%或 0.25%BNF 或 138mg/kg OPZ+0.125%BNF（n=912）6 周。在实验 2 中，雄性大鼠接受口服剂量为 138 或 276mg/kg OPZ、0.03%或 0.06%BNF 或 138mg/kg OPZ+0.03%BNF（n=1112）9 天，起始于 PH 前 1 周。作为起始治疗，2-氨基-3,4-二甲基咪唑[4,5-f]喹啉（MeIQx）在 PH 后 12 小时口服给予。大鼠在 15 天内饲喂基础饮食，然后在接下来的 10 天内用含有 0.015%2-乙酰氨基芴的饮食喂养，同时给予单次碳四氯化物口服剂量。在实验 1 中，OPZ+BNF 组的谷胱甘肽 S-转移酶胎盘形式阳性焦点的数量和面积明显高于高 OPZ 或高 BNF 组的平均值。OPZ+BNF 组肝中环氧化酶-2（Cox-2）和 COX-2 蛋白的表达显著增加。在实验 2 中，OPZ+BNF 的联合给药并未增强肝起始活性。我们的研究结果表明，OPZ 和 BNF 的联合给药可能由于 COX-2 表达增加而导致肝肿瘤促进作用协同，而对大鼠 MeIQx 的肝起始活性没有修饰作用。
