Bruner L H, Carpenter L J, Hamlow P, Roth R A
Toxicol Appl Pharmacol. 1986 Sep 30;85(3):416-27. doi: 10.1016/0041-008x(86)90349-2.
Monocrotaline (MCT) produces vascular injury to the lung, pulmonary hypertension, and right ventricular hypertrophy when injected into rats. It is well established that the pneumotoxicity of MCT depends on its hepatic bioactivation to monocrotaline pyrrole (MCTP) and perhaps other toxic metabolites. To test whether MCTP requires further bioactivation, we synthesized this metabolite chemically, confirmed its structure using fast-atom bombardment-mass spectrometry and nuclear magnetic resonance, and injected it into rats previously treated with an inducer or inhibitor of MFOs. Pretreatment with either phenobarbital or SKF-525A did not alter the pneumotoxic effects of an intravenous injection of MCTP. Rats given the same intravenous dose of either MCT, MCT N-oxide, or MCTP responded with toxicity only to MCTP. MCTP added to rat serum in vitro resulted in a color change (Amax = 477 nm) that developed over several seconds, an observation consistent with degradation of MCTP in serum. To explore the possibility that aqueous degradation products might contribute to its toxicity, the same intravenous dose of MCTP was administered to rats in N,N-dimethylformamide (DMF), serum, or saline. Only MCTP administered in in DMF resulted in toxicity. These results support the contention that MCT requires metabolism to MCTP to produce pneumotoxicity and that exposure to aqueous media renders MCTP incapable of causing lung injury.
将野百合碱（MCT）注射到大鼠体内会导致肺部血管损伤、肺动脉高压和右心室肥大。众所周知，MCT的肺毒性取决于其在肝脏中生物活化生成野百合碱吡咯（MCTP）以及可能的其他有毒代谢产物。为了测试MCTP是否需要进一步的生物活化，我们化学合成了这种代谢产物，通过快原子轰击质谱和核磁共振确认了其结构，并将其注射到先前用MFO诱导剂或抑制剂处理过的大鼠体内。用苯巴比妥或SKF - 525A预处理均未改变静脉注射MCTP的肺毒性作用。给予相同静脉剂量的MCT、MCT N - 氧化物或MCTP的大鼠中，只有MCTP产生了毒性反应。体外将MCTP添加到大鼠血清中会导致在几秒钟内出现颜色变化（最大吸收波长 = 477 nm），这一观察结果与血清中MCTP的降解一致。为了探究水解产物可能导致其毒性的可能性，将相同静脉剂量的MCTP以N，N - 二甲基甲酰胺（DMF）、血清或生理盐水的形式给予大鼠。只有以DMF形式给予的MCTP产生了毒性。这些结果支持以下观点：MCT需要代谢为MCTP才能产生肺毒性，并且暴露于水性介质会使MCTP无法导致肺损伤。
