Nishikawa Akiyoshi, Furukawa Fumio, Miyauchi Makoto, Son Hwa-Young, Okazaki Kazushi, Koide Akihiro, Mori Yukio, Hirose Masao
Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo 158-8501, Japan.
Jpn J Cancer Res. 2002 Jan;93(1):24-31. doi: 10.1111/j.1349-7006.2002.tb01196.x.
The modifying effects of cigarette smoke (CS) exposure on a heterocyclic amine (HCA) 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced carcinogenesis were investigated in male F344 rats. Groups 1 and 2 were fed MeIQx at a dose of 300 ppm, and simultaneously received CS and sham smoke (SS) for 16 weeks, respectively. Groups 3 - 5 were given the MeIQx diet for 4 weeks, and simultaneously exposed to CS for 4 weeks (group 3), exposed to CS for 12 weeks after the MeIQx treatment (group 4) or received SS for 16 weeks (group 5). Groups 6 and 7 were fed basal diet and respectively received CS and SS for 16 weeks. In terms of the mean number or area, the development of glutathione S-transferase placental form-positive (GST-P(+)) liver cell foci was significantly (P < 0.01) greater in group 1 than in group 2. The mean number of colonic aberrant crypt foci (ACFs) per animal was increased by continuous CS exposure regardless of MeIQx feeding, the differences between groups 4 and 5 (P < 0.05), and between groups 6 and 7 (P < 0.05) being significant. Immunoblot analysis confirmed that the hepatic CYP1A2 level in group 6 was remarkably increased as compared to that in group 7. In addition, liver S9 from rats in group 6 consistently increased the mutagenic activities of six HCAs including MeIQx as compared to those in group 7. Thus, our results clearly indicate that CS enhances hepatocarcinogenesis when given in the initiation phase via increasing intensity of metabolic activation for MeIQx and possibly colon carcinogenesis when given in the post-initiation phase in rats induced by MeIQx.
在雄性F344大鼠中研究了香烟烟雾（CS）暴露对杂环胺（HCA）2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）诱导的致癌作用的修饰效应。第1组和第2组以300 ppm的剂量喂食MeIQx，同时分别接受CS和假烟雾（SS）处理16周。第3 - 5组给予MeIQx饮食4周，同时暴露于CS 4周（第3组），在MeIQx处理后暴露于CS 12周（第4组）或接受SS 16周（第5组）。第6组和第7组喂食基础饮食，分别接受CS和SS 16周。就平均数量或面积而言，第1组中谷胱甘肽S-转移酶胎盘形式阳性（GST-P(+)）肝细胞灶的发生在统计学上显著高于第2组（P < 0.01）。无论是否喂食MeIQx，持续暴露于CS都会增加每只动物结肠异常隐窝灶（ACF）的平均数量，第4组和第5组之间（P < 0.05）以及第6组和第7组之间（P < 0.05）的差异具有统计学意义。免疫印迹分析证实，与第7组相比，第6组肝脏中的CYP1A2水平显著升高。此外，与第7组相比，第6组大鼠的肝脏S9始终增加包括MeIQx在内的六种HCA的诱变活性。因此，我们的结果清楚地表明，在起始阶段给予CS时，通过增加MeIQx的代谢活化强度可增强肝癌发生，而在MeIQx诱导的大鼠起始后阶段给予CS时可能增强结肠癌发生。
