Hoorn C M, Wagner J G, Roth R A
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Toxicol Appl Pharmacol. 1993 Jun;120(2):281-7. doi: 10.1006/taap.1993.1113.
Administration of monocrotaline pyrrole (MCTP), a putative toxic metabolite of the pyrrolizidine alkaloid, monocrotaline (MCT), results in delayed and progressive pneumotoxicity in the rat. It has been suggested that the lung injury caused by this compound may be initiated by an interaction between MCTP and cells of the pulmonary vasculature. A likely site for initial binding of this reactive electrophile is the pulmonary endothelium. MCTP causes direct toxicity to cultured bovine and porcine pulmonary artery endothelial cells (BECs and PECs, respectively), but there exist species differences both in whole-animal response to the parent alkaloid and in cellular response to direct application of MCTP. In this study, the changes in cultured rat pulmonary vascular endothelial cells (RECs) after a single administration of MCTP were characterized in order to compare these with changes previously identified in this species in vivo. Studies with RECs have also provided an additional model for examination of species-related differences in response to this toxicant. MCTP caused a delayed and progressive release of lactate dehydrogenase from REC monolayers. Progressive cell detachment was evident and remaining cells became enlarged, with morphologic changes comparable to those reported previously in BECs, including cytoplasmic vacuolization and nuclear enlargement. MCTP inhibited cell proliferation at concentrations of 0.05 micrograms MCTP/ml or greater, and DNA crosslinking was evident at 24 and 48 hr post-treatment. These results suggest that MCTP is directly toxic to cultured RECs, and the development of changes is reminiscent of that seen in the rat in vivo. The cytostatic nature of the compound, in combination with its cytolytic effect on RECs, could contribute to the development of pulmonary edema and other lung vascular changes seen in rats treated with MCT or MCTP.
给予单猪屎豆碱吡咯（MCTP）（一种吡咯里西啶生物碱单猪屎豆碱（MCT）的假定有毒代谢产物）会导致大鼠出现延迟性和进行性肺毒性。有人认为，该化合物引起的肺损伤可能是由MCTP与肺血管细胞之间的相互作用引发的。这种反应性亲电试剂最初结合的一个可能部位是肺内皮。MCTP对培养的牛和猪肺动脉内皮细胞（分别为BECs和PECs）具有直接毒性，但在对母体生物碱的全动物反应以及对直接应用MCTP的细胞反应方面都存在物种差异。在本研究中，对单次给予MCTP后培养的大鼠肺血管内皮细胞（RECs）的变化进行了表征，以便将这些变化与先前在该物种体内确定的变化进行比较。对RECs的研究还提供了一个额外的模型，用于检查对这种毒物反应的物种相关差异。MCTP导致RECs单层中乳酸脱氢酶的延迟性和进行性释放。明显出现进行性细胞脱离，剩余细胞变大，其形态学变化与先前在BECs中报道的变化相当，包括细胞质空泡化和核增大。MCTP在浓度为0.05微克MCTP/毫升或更高时抑制细胞增殖，并且在处理后24小时和48小时DNA交联明显。这些结果表明，MCTP对培养的RECs具有直接毒性，并且变化的发展让人联想到在大鼠体内看到的情况。该化合物的细胞抑制性质及其对RECs的细胞溶解作用，可能导致在用MCT或MCTP处理的大鼠中出现肺水肿和其他肺血管变化。
