Fennell Timothy R, Snyder Rodney W, Krol Wojciech L, Sumner Susan C J
CIIT Centers for Health Research, P.O. Box 12137, Research Triangle Park, North Carolina 27709, USA.
Toxicol Sci. 2003 Feb;71(2):164-75. doi: 10.1093/toxsci/71.2.164.
Acrylamide (AM) and N-methylolacrylamide (NMA) are used in the formulation of grouting materials. AM undergoes metabolism to a reactive epoxide, glycidamide (GA). Both AM and GA react with hemoglobin to form adducts that can be related to exposure to AM. The objective of this study was to evaluate the extent to which NMA could form the same adducts as AM. N-(2-carbamoylethyl)valine (AAVal derived from AM) and N-(2-carbamoyl-2-hydroxyethyl)valine (GAVal derived from GA) were measured following a single oral dose of AM (50 mg/kg) or NMA (71 mg/kg) in male F344 rats. AAVal and GAVal were measured by a modified Edman degradation to produce phenylthiohydantoin derivatives and liquid chromatography/tandem mass spectrometry. In AM-treated rats, AAVal was 21 +/- 1.7-pmol/mg globin (mean +/- SD, n = 4), and GAVal was 7.9 +/- 0.8 pmol/mg. In NMA-treated rats, AAVal was 41 +/- 4.9 pmol/mg, and GAVal was 1.4 +/- 0.1 pmol/mg. Whether AAVal was derived from reaction of NMA with globin followed by loss of the hydroxymethyl group, or loss of the hydroxymethyl group to form AM prior to reaction with globin, is not known. However, the higher ratio of AAVal:GAVal in NMA-treated rats (29 vs. 2.6 in AM-treated rats) suggests that reaction of NMA with globin is the predominant route to AAVal in NMA-treated rats. The detection of GAVal in NMA-treated rats indicates oxidation of NMA, either directly or following conversion to AM. The lower levels of GAVal on NMA administration suggest that a much lower level of epoxide was formed than compared with AM treatment.
丙烯酰胺（AM）和N-羟甲基丙烯酰胺（NMA）用于灌浆材料配方。AM经代谢生成活性环氧化物缩水甘油酰胺（GA）。AM和GA均与血红蛋白反应形成加合物，这些加合物可与AM暴露相关。本研究的目的是评估NMA形成与AM相同加合物的程度。在雄性F344大鼠单次口服AM（50 mg/kg）或NMA（71 mg/kg）后，测定N-（2-氨甲酰基乙基）缬氨酸（源自AM的AAVal）和N-（2-氨甲酰基-2-羟乙基）缬氨酸（源自GA的GAVal）。通过改良的埃德曼降解法生成苯硫代乙内酰脲衍生物，并用液相色谱/串联质谱法测定AAVal和GAVal。在AM处理的大鼠中：AAVal为21±1.7 pmol/mg珠蛋白（平均值±标准差，n = 4），GAVal为7.9±0.8 pmol/mg。在NMA处理的大鼠中，AAVal为41±4.9 pmol/mg，GAVal为1.4±0.1 pmol/mg。尚不清楚AAVal是源自NMA与珠蛋白反应后羟甲基的丢失，还是在与珠蛋白反应前羟甲基丢失形成AM。然而，NMA处理的大鼠中AAVal:GAVal的比例较高（29，而AM处理的大鼠中为2.6），这表明NMA与珠蛋白反应是NMA处理的大鼠中AAVal的主要生成途径。在NMA处理的大鼠中检测到GAVal表明NMA发生了氧化，可能是直接氧化，也可能是先转化为AM后再氧化。NMA给药后GAVal水平较低，表明与AM处理相比，形成的环氧化物水平要低得多。
