Dose dependence of covalent binding of acrylonitrile to tissue protein and globin in rats.
Dose dependence of covalent binding of acrylonitrile to tissue protein and globin in rats.
复制标题
丙烯腈与大鼠组织蛋白和球蛋白共价结合的剂量依赖性。
DOI：
10.1006/faat.1997.2295
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Corbett,D
中科院分区：
文献类型：
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作者：
Benz,FW;Nerland,DE;Li,J;Corbett,D
丙烯腈（AN）共价结合组织蛋白的剂量依赖性，在一个单一的急性暴露超过100倍的剂量范围，进行了测量。在较低的剂量范围内（0.0-0.95 mmol AN/kg），共价结合是AN剂量的线性函数。剂量-反应曲线的斜率表明，组织与AN的反应性相差近10倍。共价结合的相对顺序为：血液>肾脏=肝脏>前胃=脑>腺胃>肌肉。对于珠蛋白总共价结合和珠蛋白N-（2-氰乙基）缬氨酸（CE缬氨酸）加合物形成，观察到类似的剂量-反应行为。后一种加合物仅占AN加合到珠蛋白的总量的0.2%。组织蛋白结合相对于球蛋白总共价结合或球蛋白CEValine加合物的回归表明，两种球蛋白生物标志物可用作替代物来估计结合至组织蛋白的AN的量。在较高的AN剂量下，高于约1 mmol/kg，观察到共价结合剂量-反应曲线的急剧断裂。这个结值是由肝脏谷胱甘肽几乎完全耗尽和AN解毒的最终终止来解释的。已知AN的毒性在此剂量以上急剧增加。这些数据表明，AN标记的特定组织蛋白的比较高于和低于这个阈值剂量可能会提供一些了解AN诱导的毒性机制。
The dose dependence of acrylonitrile (AN) covalent binding to tissue protein, following a single acute exposure over a 100-fold range in dose, was measured. Covalent binding was a linear function of AN dose in the lower dose range (0.0–0.95 mmol AN/kg). The slopes of the dose-response curves indicated that tissues varied by nearly 10-fold in their reactivity with AN. The relative order of covalent binding was as follows: blood > kidney = liver > forestomach = brain > glandular stomach > muscle. Similar dose-response behavior was observed for globin total covalent binding and for globinN-(2-cyanoethyl)vallne (CEValine) adduct formation. The latter adduct was found to represent only 0.2% of the total AN adduction to globin. Regression of tissue protein binding versus globin total covalent binding or globin CEValine adduct indicated that both globin biomarkers could be used as surrogates to estimate the amount of AN bound to tissue protein. At higher AN doses, above approximately 1 mmol/kg, a sharp break in the covalent binding dose-response curve was observed. This knot value is explained by the nearly complete depletion of liver glutathione and the resultant termination of AN detoxification. The toxicity of AN is known to increase sharply above this dose. The data suggest that a comparison of specific tissue proteins labeled by AN above and below this threshold dose may provide some insight into the mechanism of AN-induced toxicity.