Doerge Daniel R, Twaddle Nathan C, Boettcher Melanie I, McDaniel L Patrice, Angerer Jürgen
National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, USA.
Toxicol Lett. 2007 Feb 28;169(1):34-42. doi: 10.1016/j.toxlet.2006.12.002. Epub 2006 Dec 16.
Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells, and carcinogenic in mice and rats. AA is also formed during cooking in many commonly consumed starchy foods. Our previous toxicokinetic investigations of AA and its genotoxic metabolite, glycidamide (GA), in rodents showed that AA is highly bioavailable from oral routes of administration, is widely distributed to tissues, and that the dietary route, in particular, favors metabolism to GA. Formation and accumulation of mutagenic GA-DNA adducts in many tissues support the hypothesis that AA is carcinogenic in rodent bioassays through metabolism to GA. The current investigation describes the quantification of 24 h urinary metabolites, including free AA and GA and their mercapturic acid conjugates (AAMA and GAMA, respectively), using LC/MS/MS in F344 rats and B6C3F(1) mice following a dose of 0.1 mg/kg bw given by intravenous, gavage, and dietary routes of administration. Similar groups of rodents were used previously for serum/tissue toxicokinetic and adduct determinations (DNA and hemoglobin). The goal was to investigate relationships between urinary and circulating biomarkers of exposure, toxicokinetic parameters for AA and GA, and tissue GA-DNA adducts in rodents from single doses of AA. Significant linear correlations were observed between urinary levels of AA with AAMA and GA with GAMA in the current data sets for rats and mice. Concentrations of AA and AAMA correlated significantly with average AUC values determined previously for AA in groups of rats and mice similarly dosed with AA. Urinary GA and GAMA concentrations showed significant correlations with average AUC values for GA and liver GA-DNA adducts determined previously in rats and mice similarly dosed with AA. Despite statistical significance, considerable inter-animal variability was observed in all urinary measurements, which limited the degree of correlation with either average toxicokinetic or biomarker data collected from different groups of animals. These results suggest that urinary measurements of AA and its metabolites may be useful for prediction of internal exposures to AA and GA.
丙烯酰胺（AA）是一种经过广泛研究的工业化学品，具有神经毒性，对体细胞和生殖细胞有诱变作用，在小鼠和大鼠中具有致癌性。在许多常见的淀粉类食物烹饪过程中也会形成AA。我们之前对啮齿动物体内AA及其遗传毒性代谢物环氧丙酰胺（GA）进行的毒代动力学研究表明，AA经口服给药后生物利用度很高，广泛分布于组织中，而且经饮食途径给药尤其有利于其代谢为GA。在许多组织中诱变的GA-DNA加合物的形成和积累支持了这样一种假说，即AA在啮齿动物生物测定中通过代谢为GA而具有致癌性。当前的研究描述了在F344大鼠和B6C3F(1)小鼠经静脉注射、灌胃和饮食途径给予0.1mg/kg体重剂量后，使用液相色谱/串联质谱法对24小时尿液代谢物进行定量分析，这些代谢物包括游离AA和GA及其硫醚氨酸缀合物（分别为AAMA和GAMA）。之前使用了类似的啮齿动物组进行血清/组织毒代动力学和加合物测定（DNA和血红蛋白）。目的是研究单剂量AA给药后啮齿动物尿液和循环暴露生物标志物之间的关系、AA和GA的毒代动力学参数以及组织GA-DNA加合物之间的关系。在当前大鼠和小鼠的数据集中，观察到尿液中AA与AAMA以及GA与GAMA之间存在显著的线性相关性。AA和AAMA的浓度与之前在给予相同剂量AA的大鼠和小鼠组中测定的AA平均曲线下面积（AUC）值显著相关。尿液中GA和GAMA的浓度与之前在给予相同剂量AA的大鼠和小鼠中测定的GA平均AUC值以及肝脏GA-DNA加合物显著相关。尽管具有统计学意义，但在所有尿液测量中均观察到相当大的动物个体差异，这限制了与从不同动物组收集的平均毒代动力学或生物标志物数据的相关程度。这些结果表明，对AA及其代谢物进行尿液测量可能有助于预测体内对AA和GA的暴露情况。
