Li Y, Yokoi T, Katsuki M, Wang J S, Groopman J D, Kamataki T
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Cancer Res. 1997 Feb 15;57(4):641-5.
The in vivo activation of aflatoxin B1 (AFB1) was assessed by using two transgenic mouse lines, M2 and M10, in which the human fetus-specific CYP3A7 was expressed in the kidney (M2) and the liver (M10), respectively. Male mice of 8 weeks old from these two lines were treated with a single i.p. injection of AFB1 (4 mg/kg body weight). AFB1-N7-guanine adduct was quantified by high-performance liquid chromatography. DNA damage was measured using the alkaline elution technique 2 and 6 h after AFB1 treatment. Administration of AFB1 resulted in a significantly higher level of AFB1-N7-guanine in the livers of M10 transgenic mice compared with their nontransgenic littermates (16.5 +/- 4.2 versus 10.4 +/- 1.2 ng/mg DNA, P < 0.01). The level of this biomarker was also significantly higher in the kidney of the M2 mice compared with control mice (73.0 +/- 6.3 versus 50.2 +/- 9.5 ng/mg DNA, P < 0.01). Similar results were also observed with DNA damage expressed as normalized area above curve (NAAC) in the two transgenic lineages, e.g., NAAC values were significantly higher in the livers of M10 and the kidneys of M2 mice. A dose-response relationship of NAAC values was observed in the livers of M10 mice when treated with AFB1 at different doses ranging from 1 to 16 mg/kg body weight, whereas in nontransgenic mice, only slight but not statistically significant increases of NAAC values were observed. Both the mouse CYP3A11 and GST-Yc subunit were expressed at identical levels in these transgenic lines. The results of this study present further evidence that human fetuses are also under the carcinogenic attack of AFB1 as adults if exposed to this potent carcinogen.
通过使用两种转基因小鼠品系M2和M10评估黄曲霉毒素B1（AFB1）的体内激活情况，在这两种品系中，人类胎儿特异性CYP3A7分别在肾脏（M2）和肝脏（M10）中表达。对这两个品系8周龄的雄性小鼠进行单次腹腔注射AFB1（4 mg/kg体重）处理。通过高效液相色谱法定量AFB1 - N7 - 鸟嘌呤加合物。在AFB1处理后2小时和6小时，使用碱性洗脱技术测量DNA损伤。与非转基因同窝小鼠相比，给予AFB1后，M10转基因小鼠肝脏中AFB1 - N7 - 鸟嘌呤水平显著更高（16.5±4.2对10.4±1.2 ng/mg DNA，P<0.01）。与对照小鼠相比，M2小鼠肾脏中该生物标志物水平也显著更高（73.0±6.3对50.2±9.5 ng/mg DNA，P<0.01）。在两个转基因品系中，以曲线上方归一化面积（NAAC）表示的DNA损伤也观察到类似结果，例如，M10小鼠肝脏和M2小鼠肾脏中的NAAC值显著更高。当用1至16 mg/kg体重的不同剂量AFB1处理时，在M10小鼠肝脏中观察到NAAC值的剂量 - 反应关系，而在非转基因小鼠中，仅观察到NAAC值略有增加但无统计学意义。小鼠CYP3A11和GST - Yc亚基在这些转基因品系中的表达水平相同。本研究结果进一步证明，如果暴露于这种强效致癌物，人类胎儿成年后也会受到AFB1的致癌攻击。
