Neumann H G, Birner G, Kowallik P, Schütze D, Zwirner-Baier I
Institute of Pharmacology and Toxicology, University of Würzburg, Germany.
Environ Health Perspect. 1993 Mar;99:65-9. doi: 10.1289/ehp.939965.
Arylamines, nitroarenes, and azo dyes yield a common type of metabolite, the nitroarene, which produces a hydrolyzable adduct with protein and is closely related to the critical, ultimate toxic and genotoxic metabolite. The target dose as measured by hemoglobin adducts in erythrocytes reflects not only the actual uptake from the environment but also an individual's capacity for metabolic activation and is therefore an improved dosimeter for human exposure. The usefulness of hemoglobin adducts in molecular epidemiology is now widely recognized. With regard to risk assessment, many questions need to be answered. The described experiments in rats address some of these questions. The relationship between binding to hemoglobin in erythrocytes and to proteins in plasma has been found to vary considerably for a number of diamines. The fraction of hydrolyzable adducts out of the total protein adducts formed also varies in both compartments. This indicates that the kind of circulating metabolites and their availability in different compartments is compound specific. This has to do with the complex pattern of competing metabolic pathways, and the role of N-acetylation and deacetylation is emphasized. An example of nonlinear dose dependence adds to the complexity. Analysis of hemoglobin adducts reveals interesting insights into prevailing pathways, which not only apply to the chemical, but may also be useful to assess an individual's metabolic properties. In addition, it is demonstrated that the greater part of erythrocytes and benzidine-hemoglobin adducts are eliminated randomly in rats, i.e., following first-order kinetics.
芳胺、硝基芳烃和偶氮染料会产生一种常见的代谢产物——硝基芳烃，它能与蛋白质形成可水解加合物，且与关键的、最终的毒性和遗传毒性代谢产物密切相关。通过红细胞中血红蛋白加合物测量的目标剂量不仅反映了从环境中的实际摄入量，还反映了个体的代谢激活能力，因此是一种改进的人体暴露剂量计。血红蛋白加合物在分子流行病学中的实用性现在已得到广泛认可。关于风险评估，还有许多问题需要解答。在大鼠身上进行的上述实验解决了其中一些问题。已发现，对于多种二胺而言，红细胞中血红蛋白的结合与血浆中蛋白质的结合之间的关系差异很大。两个区室中形成的总蛋白质加合物中可水解加合物的比例也有所不同。这表明循环代谢产物的种类及其在不同区室中的可利用性具有化合物特异性。这与复杂的竞争性代谢途径模式有关，同时强调了N - 乙酰化和去乙酰化的作用。非线性剂量依赖性的一个例子增加了复杂性。对血红蛋白加合物的分析揭示了对主要代谢途径的有趣见解，这些见解不仅适用于该化学物质，也可能有助于评估个体的代谢特性。此外，研究表明，大鼠体内大部分红细胞和联苯胺 - 血红蛋白加合物是随机消除的，即遵循一级动力学。
