Mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, causes a paradoxical elevation of GTP in erythrocytes of renal transplant patients

Abstract

The immunosuppressant MMF (mycophenolate mofetil) has increasingly replaced AZA (azathioprine) in renal transplantation. MMF is a prodrug of MPA (mycophenolic acid), which inhibits lymphocyte IMPDH (inosine monophosphate dehydrogenase), thereby drastically decreasing GTP concentrations essential to lymphocyte proliferation in vitro and in vivo. Erythrocyte GTP concentrations are commonly elevated in severe renal disease, but normalize following successful engraftment. Consequently, elevated GTP in renal transplant recipients might signal impending loss of immunosuppression and graft failure. In the present study, we compared erythrocyte nucleotides and plasma metabolites in two groups of 25 patients after renal transplantation, both receiving prednisolone and cyclosporin A, but one group receiving MMF and the other AZA. No patients had recent allograft biopsy evidence of rejection. Erythrocyte GTP concentrations at MMF commencement were 50.4+/-23.4 micromol/l. An increase occurred during the first 3 months after transplant when MMF was used de novo, stabilizing at 146.7+/-62.9 micromol/l after 4 months. This was significantly higher (P=2.5 x 10(-6)) than erythrocyte GTP (40.4+/-15.9 micromol/l) in the AZA group, which was essentially unchanged from values immediately after successful transplantation. The effect of MMF on erythrocyte GTP levels was reversible, since GTP levels fell when MMF therapy was terminated. The results demonstrate paradoxically high GTP concentrations in erythrocytes of renal transplant patients receiving MMF. MPA may stabilize reticulocyte IMPDH, allowing the protein to persist during erythropoiesis. This behaviour is in marked contrast with the decrease in GTP levels seen in white blood cells of patients on chronic MMF therapy.

4-Pyridone-3-carboxamide-1-β-d-ribonucleoside Triphosphate (4PyTP), a Novel NAD+ Metabolite Accumulating in Erythrocytes of Uremic Children: A Biomarker for a Toxic NAD+ Analogue in Other Tissues?

“…A similar increase in GTP (attributed to “induction” of IMPDH) was observed in patients treated with ribavirin [43]. We proposed [41] that structural stabilisation, as described by Nimmersgen et al . [44], of the IMPDH-inhibitor complex allowed a continuation of enzyme activity in non-nucleated mature erythrocytes, where new enzyme could not be synthesised.…”

“…This is reminiscent of our study of adult renal transplant patients after several months’ immunosuppressive therapy with mycophenolate mofetil, where we observed “paradoxical” high levels of GTP (approx 146 μM) in the erythrocytes [41]. We consider this to be a paradox since in other cells in the presence of mycophenolate mofetil, such as mononuclear leucocytes [42], the GTP concentrations are depleted: this is the expected result of the drug’s role as an inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH), which is crucial in the synthesis of GTP and ATP.…”

Expression of Inosine Monophosphate Dehydrogenase Type I and Type II After Mycophenolate Mofetil Treatment: A 2-year Follow-up in Kidney Transplantation

“…We have previously shown that long‐term treatment of kidney transplant patients with MMF is associated with an induction of IMPDH activity 19 . Similar but also contradictory results have been reported depending on the methodology or the biological matrix (erythrocytes versus lymphocytes) used for measuring IMPDH activity 20 , 21 , 22 , 23 , 24 , 25 . To investigate further the effect of MMF on the regulation of IMPDH, we followed, during 2 years, de novo kidney transplant recipients under triple immunosuppression regimen consisting of cyclosporine, MMF, and steroids.…”

Mycophenolate mofetil as a treatment for refractory idiopathic thrombocytopenic purpura

“…However, the mechanism requires further study. MMF selectively inhibited the proliferation and survival of lymphocytes by inducing apoptosis and suppressing glycosylation and expression of adhesion molecules such as P-selectin, etc, which were over-expressed in ITP [13] . Our result that MPA induced apoptosis of PB lymphocytes from ITP patients in vitro was consistent with a previous report [14] .…”