Ghanayem B I, Burka L T, Matthews H B
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Fundam Appl Toxicol. 1987 Oct;9(3):389-97. doi: 10.1016/0272-0590(87)90021-2.
We have demonstrated previously that ethyl acrylate causes severe acute forestomach (nonglandular portion of the stomach) toxicity in rats. Ethyl acrylate was also shown to cause forestomach tumors when administered to rats chronically by gavage. The current studies were designed to investigate ethyl acrylate distribution, excretion, and metabolism, as well as the macromolecular interactions of ethyl acrylate (EtAc) in the forestomach (target organ) and liver (nontarget organ). 2,3-[14C]Ethyl acrylate was administered in corn oil at 100, 200, or 400 mg/kg by gavage. Data presented here show that the radioactivity derived from EtAc is rapidly absorbed after gavage administration and distributed into all major tissues of male F344 rats. The highest concentration of EtAc-derived radioactivity was detected in the forestomach, glandular stomach, intestine, liver, and kidney at 4 and 24 hr after dosing. The highest percentage of EtAc-derived radioactivity was found in the lipid fraction of the liver. In the forestomach, the highest percentage of EtAc-derived radioactivity was found in the protein fraction. The major route of EtAc excretion was CO2 exhalation (approximately 70% of the administered dose in 24 hr) followed by the urinary excretion. Two metabolites were identified in the urine, namely, N-acetyl-s-(2-carboxyethyl)cysteine and N-acetyl-s-(2-carboxyethyl) cysteine ethyl ester. This suggests that Michael-like addition of sulfhydryls to acrylate is a pathway of EtAc metabolism. Hydrolysis of the ethyl ester may occur before or after conjugation. Further degradation of the GSH conjugates resulted in the formation of the mercapturic acids detected in the urine of EtAc-treated rats.
我们之前已经证明，丙烯酸乙酯会在大鼠中引起严重的急性前胃（胃的非腺性部分）毒性。当通过灌胃长期给予大鼠时，丙烯酸乙酯也被证明会导致前胃肿瘤。当前的研究旨在调查丙烯酸乙酯的分布、排泄和代谢，以及丙烯酸乙酯（EtAc）在前胃（靶器官）和肝脏（非靶器官）中的大分子相互作用。通过灌胃以100、200或400 mg/kg的剂量在玉米油中给予2,3-[¹⁴C]丙烯酸乙酯。此处呈现的数据表明，灌胃给药后，源自EtAc的放射性迅速被吸收，并分布到雄性F344大鼠的所有主要组织中。给药后4小时和24小时，在前胃、腺胃、肠道、肝脏和肾脏中检测到源自EtAc的放射性的最高浓度。在肝脏的脂质部分中发现源自EtAc的放射性的百分比最高。在前胃中，源自EtAc的放射性的百分比在蛋白质部分中最高。EtAc排泄的主要途径是呼出二氧化碳（24小时内约占给药剂量的70%），其次是尿液排泄。在尿液中鉴定出两种代谢物，即N-乙酰基-s-(2-羧乙基)半胱氨酸和N-乙酰基-s-(2-羧乙基)半胱氨酸乙酯。这表明巯基与丙烯酸酯的类似迈克尔加成反应是EtAc代谢的一条途径。乙酯水解可能在缀合之前或之后发生。谷胱甘肽缀合物的进一步降解导致在EtAc处理的大鼠尿液中检测到硫醚氨酸的形成。
