Characterization of monocrotaline pyrrole-induced DNA cross-linking in pulmonary artery endothelium.
Monocrotaline pyrrole (MCTP) is a putative, toxic metabolite of the pyrrolizidine alkaloid, monocrotaline (MCT). When given intravenously to rats, it produces a delayed and progressive injury to the vasculature of the lungs that results in pulmonary hypertension and right heart hypertrophy. Dysfunctional endothelium and vascular leak are early signs of overt injury to the lung. When administered to endothelial cell cultures, MCTP causes cell enlargement, delayed and progressive cytotoxicity, and inhibition of proliferation in surviving cells. MCTP is a bifunctional alkylating agent which binds to DNA and other macromolecules. To examine DNA-MCTP interactions in endothelium, MCTP-induced DNA cross-linking was characterized in cultures of porcine endothelial cells (PECs) derived from pulmonary artery. MCTP caused DNA cross-linking in a dose-dependent manner that was consistent with its ability to inhibit cell proliferation. PECs exposed to MCTP for 48 h developed cross-linking that was maximal at 2 days and remained significant through 10 days. Increasing the duration of PEC exposure to the medium to which MCTP had been added was associated with increased DNA cross-linking. These results indicate that MCTP causes DNA cross-linking, which may explain the inhibition of cell proliferation observed in pulmonary endothelial cells in vitro. The long-lasting nature of DNA cross-linking and its dose relatedness are consistent with the delayed and progressive effects of MCTP on endothelial cells in vitro and on pulmonary vasculature in vivo.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
J G
JG
Wagner
T W
TW
Petry
R A
RA
Roth
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D016686:Monocrotaline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011651:Pulmonary Artery; D013552:Swine; D013997:Time Factors
D003432:Cross-Linking Reagents; C014114:monocrotaline pyrrole; D016686:Monocrotaline; D004247:DNA