Calleman C J, Bergmark E, Stern L G, Costa L G
Department of Environmental Health, University of Washington, Seattle 98195.
Environ Health Perspect. 1993 Mar;99:221-3. doi: 10.1289/ehp.9399221.
Hemoglobin (Hb) adducts, formed by the neurotoxic agent acrylamide (AA) and its genotoxic metabolite glycidamide (GA), were measured in the rat by means of a method for simultaneous determination of the adducts formed to cysteine. A novel, nonlinear dosimetric model was developed to describe Hb adduct formation. This model incorporates the saturable kinetics of the metabolic conversion in vivo of AA to GA. The pharmacokinetic parameters Vmax and Km and the first-order rates of elimination, k1 and k2, for AA and GA from all processes except conversion of AA to GA, were estimated directly from Hb adduct data to 19 M hr-1, 66 microM, 0.21 hr-1, and 0.48 hr-1, respectively. At low concentrations, approximately 60% of AA was metabolized to GA. The nonlinear dosimetric model for adduct formation has potential general applicability in high-to-low-dose extrapolation of genotoxic effects.
通过一种同时测定与半胱氨酸形成的加合物的方法，在大鼠中测量了由神经毒性剂丙烯酰胺（AA）及其遗传毒性代谢物环氧丙酰胺（GA）形成的血红蛋白（Hb）加合物。开发了一种新颖的非线性剂量学模型来描述Hb加合物的形成。该模型纳入了AA在体内代谢转化为GA的饱和动力学。除了AA转化为GA的过程外，直接从Hb加合物数据估计了AA和GA的药代动力学参数Vmax和Km以及所有过程的一级消除速率k1和k2，分别为19 M hr-1、66 microM、0.21 hr-1和0.48 hr-1。在低浓度下，约60%的AA代谢为GA。加合物形成的非线性剂量学模型在遗传毒性效应的高剂量到低剂量外推中具有潜在的普遍适用性。
