Nigrovic V, Pandya J B, Klaunig J E, Fry K
Department of Anesthesiology, Medical College of Ohio, Toledo 43699.
Can J Anaesth. 1989 May;36(3 Pt 1):262-8. doi: 10.1007/BF03010762.
Cytotoxicity of atracurium and of its metabolites was tested in vitro. Exposure of isolated rat hepatocytes to atracurium produced cellular damage evidenced by extrusion of an intracellular enzyme, lactate dehydrogenase (LDH), into the incubation medium. Leakage of LDH was directly related to the concentration of atracurium in the medium (250 to 800 microM). If the spontaneous degradation of atracurium (presumably via Hofmann elimination) was first carried out in vitro and the degradation products subsequently added to the isolated hepatocytes, the leakage of LDH was also dose-dependent but larger than that observed after the addition of the parent drug. When l-cysteine was admixed to the products of the spontaneous degradation of atracurium prior to their addition to the liver cells, no leakage of LDH was observed. The results are compatible with the working hypothesis that atracurium itself and, even more so, acrylates formed in Hofmann elimination of atracurium, are reactive toward nucleophiles and damage the cells by alkylating nucleophiles present in cellular membranes. Antecedent covalent binding of acrylates to the nucleophile cysteine, i.e., the formation of acrylate-cysteine adducts, saturated the reactive capacity of acrylates for nucleophiles and thus prevented the reactive metabolites from alkylating the endogenous nucleophiles. Possible clinical consequences resulting from in vivo generation of reactive metabolites are not clear at the present time but are projected to be related to (a) the dose of atracurium administered, (b) the amount of acrylates generated, (c) the functional importance of the endogenous nucleophiles alkylated, and (d) the pathway and the speed of detoxification of atracurium and its metabolites.
在体外测试了阿曲库铵及其代谢产物的细胞毒性。将分离的大鼠肝细胞暴露于阿曲库铵会导致细胞损伤，表现为一种细胞内酶——乳酸脱氢酶（LDH）释放到孵育培养基中。LDH的泄漏与培养基中阿曲库铵的浓度（250至800微摩尔）直接相关。如果阿曲库铵的自发降解（可能通过霍夫曼消除反应）先在体外进行，然后将降解产物添加到分离的肝细胞中，LDH的泄漏也是剂量依赖性的，但比添加母体药物后观察到的泄漏量更大。当在将阿曲库铵自发降解产物添加到肝细胞之前将l-半胱氨酸与之混合时，未观察到LDH泄漏。这些结果与以下工作假设相符：阿曲库铵本身，更确切地说是阿曲库铵霍夫曼消除反应中形成的丙烯酸酯，对亲核试剂具有反应性，并通过烷基化细胞膜中存在的亲核试剂来损伤细胞。丙烯酸酯与亲核试剂半胱氨酸预先形成共价结合，即形成丙烯酸酯-半胱氨酸加合物，使丙烯酸酯对亲核试剂的反应能力饱和，从而防止反应性代谢产物烷基化内源性亲核试剂。目前尚不清楚体内产生反应性代谢产物可能导致的临床后果，但预计与以下因素有关：（a）阿曲库铵的给药剂量，（b）产生的丙烯酸酯量，（c）被烷基化的内源性亲核试剂的功能重要性，以及（d）阿曲库铵及其代谢产物的解毒途径和速度。
