Roberts A E, Kedderis G L, Turner M J, Rickert D E, Swenberg J A
Department of Biochemical Toxicology and Pathobiology, Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Carcinogenesis. 1991 Mar;12(3):401-4. doi: 10.1093/carcin/12.3.401.
Acrylonitrile (ACN) has been shown to cause tumors of the brain, stomach and Zymbal's gland in rats in several bioassays, but it has not been tested in other species. The carcinogenic risk of humans exposed to ACN is unclear. ACN is metabolized in the liver to 2-cyanoethylene oxide (CEO), which is believed to be the proximate or ultimate carcinogenic species. Therefore, the kinetics of CEO formation were studied with liver and lung microsomes from mice and humans using a GC-MS assay for CEO, and the data were compared with previously obtained kinetic parameters for rat microsomal enzymes. The rate of CEO formation by human liver microsomes was comparable to that of rat liver microsomes, but less than that of mouse liver microsomes. Liver microsomes produced more CEO than lung microsomes with all three species. CEO formation by microsomes from mice was approximately 4 times greater than that by microsomes from rats or humans, suggesting that mice would have higher CEO concentrations in blood than rats after ACN exposure. However, after oral administration of ACN, the concentration of CEO in mouse blood was one-third that in rat blood at all doses and time points examined. These results show that CEO circulates via the blood, providing exposure to distant sites. The blood concentrations of CEO do not appear to correlate with rates of microsomal CEO formation. This suggests that species differences in the detoxication of CEO may play an important role in determining circulating CEO concentrations and distant organ exposure.
在多项生物测定中，已证实丙烯腈（ACN）可导致大鼠出现脑肿瘤、胃肿瘤和齐默尔氏腺肿瘤，但尚未在其他物种中进行测试。人类接触ACN的致癌风险尚不清楚。ACN在肝脏中代谢为2-氰基环氧乙烷（CEO），据信这是直接或最终的致癌物质。因此，使用GC-MS法检测CEO，研究了小鼠和人类肝脏及肺微粒体中CEO的生成动力学，并将数据与先前获得的大鼠微粒体酶动力学参数进行了比较。人肝微粒体中CEO的生成速率与大鼠肝微粒体相当，但低于小鼠肝微粒体。在所有三个物种中，肝微粒体产生的CEO均多于肺微粒体。小鼠微粒体产生的CEO约为大鼠或人类微粒体的4倍，这表明ACN暴露后，小鼠血液中的CEO浓度会高于大鼠。然而，口服ACN后，在所有检测剂量和时间点，小鼠血液中CEO的浓度均为大鼠血液中的三分之一。这些结果表明，CEO通过血液循环，使远处部位暴露。CEO的血液浓度似乎与微粒体中CEO的生成速率无关。这表明，CEO解毒的物种差异可能在决定循环中CEO的浓度和远处器官暴露方面发挥重要作用。
