A NONLINEAR DOSIMETRIC MODEL FOR HEMOGLOBIN ADDUCT FORMATION BY THE NEUROTOXIC AGENT ACRYLAMIDE AND ITS GENOTOXIC METABOLITE GLYCIDAMIDE
A NONLINEAR DOSIMETRIC MODEL FOR HEMOGLOBIN ADDUCT FORMATION BY THE NEUROTOXIC AGENT ACRYLAMIDE AND ITS GENOTOXIC METABOLITE GLYCIDAMIDE
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DOI：
10.2307/3431486
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发表时间：
1993-03-01
影响因子：
10.4
通讯作者：
COSTA, LG
中科院分区：
文献类型：
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作者：
CALLEMAN, CJ;BERGMARK, E;COSTA, LG
用同时测定血红蛋白与半胱氨酸形成加合物的方法，测定了神经毒剂丙烯酰胺（AA）及其遗传毒性代谢产物缩水甘油酰胺（GA）在大鼠体内形成的血红蛋白（Hb）加合物。一种新的，非线性剂量学模型来描述血红蛋白加合物的形成。该模型结合了AA到GA的体内代谢转化的饱和动力学。从Hb加合物数据直接估计AA和GA的药代动力学参数V（max）和K（m）以及一级消除速率k1和k2（除了AA转化为GA外），分别为19 M hr-1、66 mM、0.21 hr-1和0.48 hr-1。在低浓度下，大约60%的AA被代谢为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。
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 V(max) and K(m) 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 mM, 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.