Nigrovic V, Klaunig J E, Smith S L, Schultz N E
Anesth Analg. 1987 Jun;66(6):512-6.
This study tested the hypothesis that the esters of acrylic acid might be responsible for the previously observed cytotoxic effect of atracurium. Rats were pretreated with triorthotolyl phosphate (TOTP), an inhibitor of the hydrolytic degradation of atracurium. Because hydrolysis of acrylates is also inhibited by TOTP and because the hydrolysis represents a detoxification pathway for these esters, we postulated that the leak of lactic dehydrogenase (LDH) induced by atracurium would be enhanced in hepatocytes harvested from rats pretreated with TOTP. Hepatocytes isolated from rats previously treated with TOTP (25 or 50 mg/kg intraperitoneally, 20 hr before induced death) were incubated for 4 hr in the absence of muscle relaxants or in the presence of either atracurium (0.008-0.8 mM) or metocurine (0.015-0.85 mM). Atracurium produced a concentration-dependent leakage of LDH. The leakage out of cells obtained from TOTP-pretreated rats was greater than was the leakage out of hepatocytes harvested from animals pretreated only with corn oil (a vehicle for TOTP). Metocurine did not produce a leak of LDH. It is concluded that the LDH leakage was produced by ester-type products of atracurium degradation. Acrylates appear to be the toxic agent.
丙烯酸酯可能是此前观察到的阿曲库铵细胞毒性作用的原因。用磷酸三邻甲苯酯（TOTP）对大鼠进行预处理，TOTP是一种阿曲库铵水解降解的抑制剂。由于丙烯酸酯的水解也会被TOTP抑制，且水解是这些酯的解毒途径，我们推测，在经TOTP预处理的大鼠所采集的肝细胞中，阿曲库铵诱导的乳酸脱氢酶（LDH）泄漏会增强。将此前用TOTP（腹腔注射25或50 mg/kg，诱导死亡前20小时）处理过的大鼠分离得到的肝细胞，在不存在肌肉松弛剂的情况下，或在存在阿曲库铵（0.008 - 0.8 mM）或美索库铵（0.015 - 0.85 mM）的情况下孵育4小时。阿曲库铵导致LDH呈浓度依赖性泄漏。从经TOTP预处理的大鼠获得的细胞中的泄漏量，大于仅用玉米油（TOTP的溶剂）预处理的动物所采集的肝细胞中的泄漏量。美索库铵未导致LDH泄漏。得出的结论是，LDH泄漏是由阿曲库铵降解的酯类产物引起的。丙烯酸酯似乎是毒性剂。
