Reid M J, Dunston S K, Lamé M W, Wilson D W, Morin D, Segall H J
Department of Molecular Biosciences, College of Veterinary Medicine, University of California-Davis 95616, USA.
Res Commun Mol Pathol Pharmacol. 1998 Jan;99(1):53-68.
After being dehydrogenated by cytochrome P450 enzymes in the liver, monocrotaline's highly-reactive pyrrole metabolite, dehydromonocrotaline, is believed to interact with pulmonary artery endothelial cells to initiate a pulmonary vascular toxicity resembling pulmonary hypertension. Glutathione, an abundant antioxidant in pulmonary artery endothelial cells, has been shown to react with and detoxify the pyrrolic metabolites derived from monocrotaline in the liver. Using high-performance liquid chromatography with electrochemical detection, glutathione levels were measured in a time- and dose-dependent manner in human pulmonary artery endothelial cells following treatment with dehydromonocrotaline, dehydroretronecine and N-ethylmaleimide and bovine pulmonary artery endothelial cells after treatment with dehydromonocrotaline. The bovine cells had 40% less glutathione than the human in the control groups. Bovine pulmonary artery endothelial glutathione levels were depleted 20% more than the human at 15 minutes when treated with 100 microM dehydromonocrotaline. 15 microM N-ethylmaleimide caused an 80% depletion of glutathione compared to a 30% depletion with 15 microM dehydromonocrotaline in human pulmonary artery endothelial cells.
在肝脏中被细胞色素P450酶脱氢后，野百合碱的高反应性吡咯代谢产物——脱氢野百合碱，被认为与肺动脉内皮细胞相互作用，引发类似肺动脉高压的肺血管毒性。谷胱甘肽是肺动脉内皮细胞中一种丰富的抗氧化剂，已被证明能与肝脏中源自野百合碱的吡咯代谢产物发生反应并使其解毒。使用高效液相色谱-电化学检测法，在用脱氢野百合碱、脱氢倒千里光裂碱和N-乙基马来酰亚胺处理后的人肺动脉内皮细胞以及用脱氢野百合碱处理后的牛肺动脉内皮细胞中，以时间和剂量依赖的方式测量了谷胱甘肽水平。对照组中，牛细胞的谷胱甘肽比人细胞少40%。在用100微摩尔脱氢野百合碱处理时，15分钟后牛肺动脉内皮细胞的谷胱甘肽水平比人细胞多消耗20%。在人肺动脉内皮细胞中，15微摩尔N-乙基马来酰亚胺导致谷胱甘肽消耗80%，而15微摩尔脱氢野百合碱导致谷胱甘肽消耗30%。
