Alterations of endothelial nucleotide levels by mycophenolic acid result in changes of membrane glycosylation and E-selectin expression

The effect of the inhibitor of inosine-5'-monophosphate dehydrogenase (IMPD H). mycophenolic acid, on intracellular nucleotides and the synthesis of ce llular glycoproteins was evaluated in human umbilical vein endothelial cell s. A clinically attainable concentration (10 mu mol/l) of mycophenolic acid decreased guanosine-5'-triphosphate (GTP) levels significantly and led to a strong elevation of uridine-5'-triphosphate (UTP), whereas intracellular adenosine-5'-triphosphate (ATP) pools remained unaffected. The staining of the endothelial cell membranes with lectins specific for fucose and mannose (Ulex europaeus- and Galanthus nivalis agglutinin, respectively) was reduc ed, reflecting an inhibition of fucose and mannose incorporation into endot helial glycoproteins. The surface expression of E-selectin, an important de terminant for leuko-endothelial interactions decreased significantly. Guani ne and guanosine prevented the actions of mycophenolic acid and reversed th e drug-induced decrease in GTP and its associated effects. The findings tha t mycophenolic acid produces alterations in the formation off glycoproteins and in the membrane architecture are indicative of metabolic lesions induc ed by an agent that depresses guanine nucleotide synthesis through inhibtio n of IMPDH. The pronounced reduction of E-selectin surface expression on en dothelial cells accompanied by changes of endothelial cell fucosylation, a prerequisite for the contact with lymphocytic L-selectin, indicates an inhi bitory effect of mycophenolic acid in the rolling phase of leukocyte recrui tment and strongly implies a new and additional immunosuppressive mechanism of this agent.