FORMATION OF HEMOGLOBIN ADDUCTS OF ACRYLAMIDE AND ITS EPOXIDE METABOLITE GLYCIDAMIDE IN THE RAT
FORMATION OF HEMOGLOBIN ADDUCTS OF ACRYLAMIDE AND ITS EPOXIDE METABOLITE GLYCIDAMIDE IN THE RAT
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DOI：
10.1016/0041-008x(91)90036-e
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发表时间：
1991-11-01
影响因子：
3.8
通讯作者：
COSTA, LG
中科院分区：
文献类型：
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作者：
BERGMARK, E;CALLEMAN, CJ;COSTA, LG
建立了一种测定神经毒性物质丙烯酰胺及其致突变的环氧化物代谢物缩水甘油酰胺形成的血红蛋白（Hb）加合物的方法。该方法采用气相色谱/质谱法同时测定两种试剂在水解血红蛋白样品中形成的半胱氨酸加合物。给大鼠注射0 ~ 100 mg/kg体重剂量的丙烯酰胺或丙烯酰胺，测定血红蛋白加合物水平。丙烯酰胺与半胱氨酸的血红蛋白结合指数为6400 pmol (g Hb)−1/μmol (kg body wt)−1，高于迄今为止在大鼠身上研究的任何其他物质，而丙烯酰胺的血红蛋白结合指数为1820 pmol (g Hb)−1/μmol (kg body wt)−1。在注射丙烯酰胺的大鼠中，母体化合物的加合物的形成与剂量（0-100 mg/kg）大致呈线性关系，而环氧化物代谢物丙烯酰胺的加合物则呈凹曲线，可能反映了其形成的Michaelis-Menten动力学。在体外测定半胱氨酸加合物形成速率常数的基础上，利用线性动力学模型，估计丙烯酰胺和甘油酰胺从大鼠血室中消除的一级速率分别为0.37和0.48 hr−1。进一步估计，丙烯酰胺在大鼠体内转化为缩水甘油酰胺的百分比从5mg /kg剂量后的51%下降到100mg /kg剂量后的13%。用丙烯酰胺对大鼠进行亚慢性治疗（10 mg/kg/天，连续10天或3.3 mg/kg/天，连续30天）证实，根据血红蛋白加合物的形成，低剂量给药时丙烯酰胺转化为甘油酰胺的速率更高。这些发现表明，剂量率效应可能显著影响该化合物的风险估计，对于母体化合物丙烯酰胺和代谢物甘酰胺诱导的影响，应采用不同的低剂量外推程序。
A method was developed for the determination of hemoglobin (Hb) adducts formed by the neurotoxic agent acrylamide and its mutagenic epoxide metabolite glycidamide. The method was based on simultaneous measurements of the cysteine adducts formed by these two agents by means of gas chromatography/mass spectrometry in hydrolyzed hemoglobin samples. Rats were injected ip with acrylamide or glycidamide in doses ranging from 0 to 100 mg/kg body wt, and the hemoglobin adduct levels were determined. The hemoglobin binding index of acrylamide to cysteine was found to be 6400 pmol (g Hb)−1/μmol (kg body wt)−1, higher than for any other substance studied so far in the rat, and 1820 pmol (g Hb)−1/μmol (kg body wt)−1for glycidamide. In rats injected with acrylamide, formation of adducts of the parent compound was approximately linear with dose (0–100 mg/kg), whereas adducts of the epoxide metabolite glycidamide generated a concave curve, presumably reflecting the Michaelis-Menten kinetics of its formation. On the basis of the rate constants for cysteine adduct formation determined in vitro, the first-order rates of elimination of acrylamide and glycidamide from the blood compartment of rats were estimated to be 0.37 and 0.48 hr−1, respectively, using a linear kinetic model. It was further estimated that the percentage of acrylamide converted to glycidamide in the rat decreased from 51% following administration of 5 mg/kg to 13% after a dose of 100 mg/kg. Subchronic treatment of rats with acrylamide (10 mg/kg/day for 10 days or 3.3 mg/kg/day for 30 days) confirmed that the conversion rate of acrylamide to glycidamide, as determined from hemoglobin adduct formation, is higher at low-administered doses. These findings suggest that dose-rate effects may significantly affect risk estimates of this compound and that different low-dose extrapolation procedures should be employed for effects induced by the parent compound acrylamide and those induced by the metabolite glycidamide.