Azathioprine and 6-mercaptopurine alter the nucleotide balance in endothelial cells.
Graft vascular disease after solid organ transplantation is a main complication that limits long-term survival of the graft. An injury of the endothelium and subsequent vascular response is considered to be responsible for smooth muscle cell hyperplasia with resulting luminal narrowing. What is less certain are the precise steps leading to endothelial injury and subsequent vessel disease. Since the immunosuppressive drug azathioprine is in clinical use due to its antiproliferative effect on lymphocytes, we were interested in how far it exerts effects on the vascular endothelium. Azathioprine and its metabolite 6-mercaptopurine, a potent inhibitor of purine salvage pathway enzymes, dose dependently led to decreased endothelial cell proliferation as well as to decreases in intracellular purine nucleotides adenosine-triphosphate and guanosine-triphosphate. By increasing the formation of the pyrimidine nucleotide uridine-triphosphate within 24 hours, azathioprine and its metabolite altered the endothelial nucleotide balance. Since not only the formation of toxic thio- and methylthiopurines (thio-guanosine-monophosphate, methyl-thio-inosine-monophosphate) was measured, the activity of the enzyme thiopurinemethyltransferase was induced (3.21+/-2.04 U per 10(9) cells, mean+/-SD). These findings indicate that the vascular endothelium plays an active role in the metabolization of the established immunosuppressant azathioprine that then exerts specific toxic effects on endothelial cells.
Weigel
G
G
Department of Cardiothoracic Surgery, University of Vienna, Austria.
Griesmacher
A
A
DeAbreu
R A
RA
Wolner
E
E
Mueller
M M
MM
D001379:Azathioprine / Q000494:pharmacology*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015122:Mercaptopurine / Q000494:pharmacology*; D008780:Methyltransferases / Q000378:metabolism; D011687:Purines / Q000378:metabolism*; D014472:Umbilicus
D007166:Immunosuppressive Agents; D011687:Purines; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D005978:Glutathione; D001379:Azathioprine