Peter Bertalanffy, Peter Dubsky, Ernst Wolner, Guenter Weigel
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 (IMPDH), mycophenolic acid, on
intracellular nucleotides and the synthesis of cellular
glycoproteins was evaluated in human umbilical vein
endothelial cells. A clinically attainable concentration
(10 ?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 reduced, reflecting an
inhibition of fucose and mannose incorporation into
endothelial glycoproteins. The surface expression of
E-selectin, an important determinant for leuko-endothelial
interactions decreased significantly. Guanine
and guanosine prevented the actions of mycophenolic
acid and reversed the drug-induced decrease in GTP
and its associated effects. The findings that mycophenolic
acid produces alterations in the formation of glycoproteins
and in the membrane architecture are indicative
of metabolic lesions induced by an agent that
depresses guanine nucleotide synthesis through inhibtion
of IMPDH. The pronounced reduction of E-selectin
surface expression on endothelial cells accompanied
by changes of endothelial cell fucosylation, a
prerequisite for the contact with lymphocytic L-selectin,
indicates an inhibitory effect of mycophenolic acid
in the rolling phase of leukocyte recruitment and
strongly implies a new and additional immunosuppressive
mechanism of this agent.
Clinical Chemical Laboratory Medicine, Walter de Gruyter
Print ISSN: 1434-6621
Volume: 37, 03/1999
Pages: 259 - 264
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