Comparison of the hemoglobin adducts formed by administration of N-methylolacrylamide and acrylamide to rats
Comparison of the hemoglobin adducts formed by administration of N-methylolacrylamide and acrylamide to rats
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DOI：
10.1093/toxsci/71.2.164
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发表时间：
2003-02-01
影响因子：
3.8
通讯作者：
Sumner, SCJ
中科院分区：
文献类型：
--
作者：
Fennell, TR;Snyder, RW;Sumner, SCJ
采用丙烯酰胺（AM）和n -甲基丙烯酰胺（NMA）配制注浆材料。AM代谢为活性环氧化物，甘油酸（GA）。AM和GA都与血红蛋白反应形成与AM暴露有关的加合物。本研究的目的是评估NMA可以形成与AM相同的加合物的程度。在雄性F344大鼠单次口服AM （50 mg/kg）或NMA （71 mg/kg）后，测定N-（2-氨基甲酰乙基）缬氨酸（来源于AM的AAVal）和N-（2-氨基甲酰-2-羟乙基）缬氨酸（来源于GA的GAVal）。采用改进的Edman降解法制备苯硫代海因衍生物和液相色谱/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+/- SD， 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。目前尚不清楚AAVal是由NMA与珠蛋白反应后羟甲基的丢失而产生的，还是在与珠蛋白反应前羟甲基的丢失而形成AM。然而，NMA处理大鼠中AAVal:GAVal的比例较高（29比2.6），这表明NMA与珠蛋白的反应是NMA处理大鼠中AAVal的主要途径。NMA处理大鼠的GAVal检测表明NMA氧化，直接或随后转化为AM。NMA处理的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。
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.