Koepke S R, Creasia D R, Knutsen G L, Michejda C J
Laboratory of Chemical and Physical Carcinogenesis, National Cancer Institute-Frederick Cancer Research Facility, Maryland 21701.
Cancer Res. 1988 Mar 15;48(6):1533-6.
The carcinogenicity of N-nitrosomethyl-(2-hydroxyethyl)amine (NMHEA), N-nitrosomethyl-(3-hydroxypropyl)amine (NMHPA), and the p-toluenesulfonate (tosylate) ester of NMHEA (NMHEATs) was tested in male and female F344 rats. The chemicals (25.6 mumol per application) were administered by twice-weekly gavage in corn oil (0.2 ml) for the lifetime of the animals. NMHEA was found to be an effective carcinogen under those conditions. The median survival time for the females was 9 mo after treatment was initiated, while for the males it was 12 mo. The principal cause of death of the females was hepatocellular carcinoma (14 of 20), while only 6 of 20 male rats exhibited that tumor. A few of the male rats had squamous cell carcinomas of the nasal epithelium (4 of 20), tumors which were not observed in the females. NMHPA was a much weaker carcinogen. Many of these rats survived for 2 yr and most had many age-related cancers. Nevertheless, 10 of the NMHPA-treated males and 2 females had adenocarcinoma of the lung, which was absent in the controls and also induced a significant number of neoplastic nodules in the livers of rats of both sexes. NMHEATs was also a weak carcinogen. However, besides many age-related tumors, it induced some hepatocellular carcinomas as well as hemangiosarcomas of the liver. NMHEATs was at least partially hydrolyzed to NMHEA, which was detected in the blood plasma of treated rats. A hypothesis has been advanced that NMHEA is activated to a proximate carcinogen by sulfate conjugation of the hydroxyl group; the present data do not contradict this hypothesis. The relatively lower carcinogenic potency of NMHPA, the different tumor spectrum induced by this chemical, and particularly the differences in chemical behavior suggest that its mode of activation is not the same as that for NMHEA.
在雄性和雌性F344大鼠中测试了N-亚硝基甲基-(2-羟乙基)胺（NMHEA）、N-亚硝基甲基-(3-羟丙基)胺（NMHPA）以及NMHEA的对甲苯磺酸盐（甲苯磺酸盐）酯（NMHEATs）的致癌性。这些化学物质（每次应用25.6微摩尔）在玉米油（0.2毫升）中通过每周两次灌胃给药，持续动物的一生。在这些条件下，发现NMHEA是一种有效的致癌物。雌性大鼠开始治疗后的中位生存时间为9个月，而雄性为12个月。雌性大鼠的主要死亡原因是肝细胞癌（20只中有14只），而20只雄性大鼠中只有6只出现该肿瘤。少数雄性大鼠有鼻上皮鳞状细胞癌（20只中有4只），雌性大鼠未观察到这种肿瘤。NMHPA是一种弱得多的致癌物。这些大鼠中的许多存活了2年，大多数患有许多与年龄相关的癌症。然而，接受NMHPA治疗的雄性大鼠中有10只和雌性大鼠中有2只患有肺癌腺癌，对照组中没有这种癌症，并且在两性大鼠的肝脏中也诱导出大量肿瘤结节。NMHEATs也是一种弱致癌物。然而，除了许多与年龄相关的肿瘤外，它还诱导了一些肝细胞癌以及肝血管肉瘤。NMHEATs至少部分水解为NMHEA，在接受治疗的大鼠血浆中检测到了NMHEA。有人提出一种假设，即NMHEA通过羟基的硫酸结合被激活为近端致癌物；目前的数据并不与这一假设相矛盾。NMHPA相对较低的致癌效力、这种化学物质诱导的不同肿瘤谱，特别是化学行为的差异表明其激活模式与NMHEA不同。
