Azathioprine and 6-mercaptopurine alter the nucleotide balance in endothelial cells

Graft vascular disease after solid organ transplantation is a main complica tion that limits long-term survival of the graft. An injury of the endothel ium and subsequent vascular response is considered to be responsible for sm ooth 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 clinic al use due to its antiproliferative effect on lymphocytes, we were interest ed in how far it exerts effects on the vascular endothelium, Azathioprine a nd its metabolite 6-mercaptopurine, a potent inhibitor of purine salvage pa thway enzymes, dose dependently led to decreased endothelial cell prolifera tion 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 a nd its metabolite altered the endothelial nucleotide balance. Since not onl y the formation of toxic thio- and methylthiopurines (thio-guanosine-monoph osphate, methyl-thio-inosine-monophosphate) was measured, the activity of t he enzyme thiopurinemethyltransferase was induced (3.21+/-2.04 U per 10(9) cells, mean+/-SD). These findings indicate that the vascular endothelium pl ays an active role in the metabolization of the established immunosuppressa nt azathioprine that then exerts specific toxic effects on endothelial cell s. (C) 1999 Elsevier Science Ltd. All rights reserved.