Hakura A, Tsutsui Y, Sonoda J, Kai J, Imade T, Shimada M, Sugihara Y, Mikami T
Drug Safety Research Laboratories, Ibaraki, Japan.
Mutat Res. 1998 Feb 26;398(1-2):123-30. doi: 10.1016/s0027-5107(97)00248-0.
To evaluate whether the in vivo mutagenicity test system using the lacZ transgenic mice (Muta Mouse) may be applied to carcinogenesis studies, both the in vivo mutagenicity and carcinogenicity of benzo[a]pyrene (BP) was tested in mice under the same administration conditions. The eleven organs of the mice on the 14th day after the final oral administration of BP at a dose of 125 mg kg(-1) day(-1) or corn oil for 5 consecutive days were tested for in vivo mutation by the positive-selection method. The data show that the colon had the highest lacZ mutant frequency (37-fold increase over the spontaneous frequency), followed by the ileum > forestomach > bone marrow, spleen > glandular stomach > liver, lung > kidney and heart. No significant mutations were found in the brain. These results may suggest that, in general, the organs with rapidly proliferative tissues have a marked increase in vivo mutant frequencies under the conditions of this experimental design. The forestomach and lymphatic organs including the spleen (malignant lymphoma) were the main target organs for BP carcinogenesis by 5 daily oral doses of 75 and 125 mg kg(-1) day(-1). These results suggest that the mutation results from the transgenic assay with BP reflect the carcinogenicity of BP in the mouse. They also indicate, however, that the magnitude of the in vivo lacZ mutant frequencies induced by BP in different organs did not fully correlate with the target organs for carcinogenicity.
为了评估使用lacZ转基因小鼠（突变小鼠）的体内诱变性测试系统是否可应用于致癌研究，在相同给药条件下对小鼠进行了苯并[a]芘（BP）的体内诱变性和致癌性测试。以125 mg kg⁻¹天⁻¹的剂量或玉米油连续5天对小鼠进行末次口服给药后第14天，对小鼠的11个器官采用阳性选择法进行体内突变检测。数据显示，结肠的lacZ突变频率最高（比自发频率增加37倍），其次是回肠＞前胃＞骨髓、脾脏＞腺胃＞肝脏、肺＞肾脏和心脏。在大脑中未发现明显突变。这些结果可能表明，一般来说，在本实验设计条件下，具有快速增殖组织的器官体内突变频率显著增加。前胃和包括脾脏（恶性淋巴瘤）在内的淋巴器官是通过每天口服5次75和125 mg kg⁻¹天⁻¹的BP进行致癌作用的主要靶器官。这些结果表明，BP转基因检测的突变结果反映了BP在小鼠体内的致癌性。然而，它们也表明，BP在不同器官中诱导的体内lacZ突变频率的大小与致癌靶器官并不完全相关。
