Effect of monocrotaline metabolites on glutathione levels in human and bovine pulmonary artery endothelial cells.
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.
Reid
M J
MJ
Department of Molecular Biosciences, College of Veterinary Medicine, University of California-Davis 95616, USA.
Dunston
S K
SK
Lamé
M W
MW
Wilson
D W
DW
Morin
D
D
Segall
H J
HJ
D000704:Analysis of Variance; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005033:Ethylmaleimide / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D016686:Monocrotaline / Q000031:analogs & derivatives* / Q000633:toxicity; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors
C014114:monocrotaline pyrrole; D016686:Monocrotaline; D005978:Glutathione; D005033:Ethylmaleimide; C007241:dehydroretronecine