Hagiwara A, Matsuda T, Tamano S, Kitano M, Imaoka S, Funae Y, Takesada Y, Shirai T, Fukushima S
Daiyu-kai Institute of Medical Science, Nishiazai, Azai-cho, Ichinomiya, Japan.
Cancer Lett. 1996 Dec 20;110(1-2):155-62. doi: 10.1016/s0304-3835(96)04478-3.
The dose-response relationship between liver tumor promoting activity and cytochrome P-450 (CYP) induction by phenobarbital sodium (PB) was investigated using the liver medium-term bioassay system of Ito. Two weeks after a single dose of N-nitrosodiethylamine (DEN) (200 mg/kg body weight, i.p.), rats were given PB at dietary levels of 500, 250, 125, 60, 30, 15 and 8 parts per million (ppm) for 6 weeks. All rats were subjected to partial hepatectomy at week 3, and were killed at week 8. Quantitative values for glutathione S-transferase placental form positive hepatocytic (GST-P+) foci were increased in the high dose groups dose-dependently. In contrast, the values in the low dose groups were rather lower than that of the control. CYP2B1, 2C6 and 3A2 were predominantly immunostainable in hepatocytes around the central vein. While Western blotting revealed CYP2B1 and 2C6 proteins to be increased with strict dose-dependence, CYP3A2 was only elevated at high doses. Thus, a good correlation between increase of GST-P+ foci and CYP3A2 induction was observed, as well as with CYP2B1 and 2C6 in high dose groups.
利用伊藤肝脏中期生物测定系统，研究了苯巴比妥钠（PB）诱导细胞色素P - 450（CYP）与肝脏肿瘤促进活性之间的剂量反应关系。单次腹腔注射N - 亚硝基二乙胺（DEN）（200 mg/kg体重）两周后，给大鼠喂食含500、250、125、60、30、15和8 ppm PB的饲料，持续6周。所有大鼠在第3周接受部分肝切除术，并在第8周处死。高剂量组中谷胱甘肽S - 转移酶胎盘型阳性肝细胞灶（GST - P +）的定量值呈剂量依赖性增加。相比之下，低剂量组的值比对照组低。CYP2B1、2C6和3A2主要在中央静脉周围的肝细胞中可免疫染色。虽然蛋白质印迹法显示CYP2B1和2C6蛋白的增加具有严格的剂量依赖性，但CYP3A2仅在高剂量时升高。因此，观察到GST - P +灶的增加与CYP3A2的诱导之间存在良好的相关性，在高剂量组中与CYP2B1和2C6也存在良好相关性。
