Fujita Ken-ichi, Ohnishi Takamasa, Sekine Kazunori, Iigo Masaaki, Tsuda Hiroyuki
Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045.
Jpn J Cancer Res. 2002 Jun;93(6):616-25. doi: 10.1111/j.1349-7006.2002.tb01299.x.
The inhibitory influence of bovine lactoferrin (bLF) on induction of preneoplastic hepatic glutathione S-transferase placental form-positive (GST-P( +)) cell foci and colon aberrant crypt foci (ACF) by diethylnitrosamine (DEN) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in F344 rats. Rats were initially treated with DEN, then placed on basal diet containing MeIQx (200 ppm) alone, MeIQx plus 2% bLF, or MeIQx plus 0.2% bLF from week 2 to week 8, with partial hepatectomy performed at week 3. Concomitant administration of 2% or 0.2% bLF with MeIQx caused significant dose-dependent decreases in both number and unit area of GST-P(+) cell foci (2% bLF, P < 0.001; 0.2% bLF, P < 0.01). Similar results were observed for MeIQx-induced colon ACF in the groups without DEN treatment (2% and 0.2% bLF, P < 0.05). To investigate the underlying mechanisms, we analyzed the influence of bLF on levels of cytochrome P4501A2 (CYP1A2), a metabolically activating enzyme of MeIQx in the liver. The results demonstrated that combined administration of 2% bLF significantly reduced levels of MeIQx-induced CYP1A2 mRNA (P < 0.05) and protein (P < 0.05) to the normal levels, in association with reduced values for MeIQx-DNA adducts (P < 0.05), liver GST-P(+) cell foci and colon ACF. These results suggest that bLF is a chemopreventive agent for DEN alone or DEN plus MeIQx-induced liver, and MeIQx-induced colon carcinogenesis in rats. One possible mechanism is a normalizing down-regulation of CYP1A2 expression by bLF, with consequent reduction of carcinogen activation and adduct formation.
在F344大鼠中研究了牛乳铁蛋白（bLF）对二乙基亚硝胺（DEN）和2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）诱导的癌前肝谷胱甘肽S-转移酶胎盘形式阳性（GST-P(+)）细胞灶和结肠异常隐窝灶（ACF）的抑制作用。大鼠最初用DEN处理，然后从第2周到第8周置于仅含MeIQx（200 ppm）、MeIQx加2% bLF或MeIQx加0.2% bLF的基础饮食中，并在第3周进行部分肝切除术。与MeIQx同时给予2%或0.2% bLF导致GST-P(+)细胞灶的数量和单位面积均出现显著的剂量依赖性下降（2% bLF，P < 0.001；0.2% bLF，P < 0.01）。在未用DEN处理的组中，对于MeIQx诱导的结肠ACF也观察到类似结果（2%和0.2% bLF，P < 0.05）。为了研究潜在机制，我们分析了bLF对细胞色素P4501A2（CYP1A2）水平的影响，CYP1A2是MeIQx在肝脏中的代谢活化酶。结果表明，联合给予2% bLF可使MeIQx诱导的CYP1A2 mRNA（P < 0.05）和蛋白质（P < 0.05）水平显著降低至正常水平，同时MeIQx-DNA加合物值降低（P < 0.05），肝脏GST-P(+)细胞灶和结肠ACF也减少。这些结果表明，bLF是一种对DEN单独或DEN加MeIQx诱导的大鼠肝癌以及MeIQx诱导的大鼠结肠癌的化学预防剂。一种可能的机制是bLF对CYP1A2表达进行正常化下调，从而减少致癌物活化和加合物形成。
