Effect of mycophenolate mofetil therapy on inosine monophosphate dehydrogenase induction in red blood cells of heart transplant recipients.
BACKGROUND
Mycophenolic acid is reported to provide effective immunosuppression by inhibiting inosine monophosphate dehydrogenase. In an attempt to monitor the biological effects of long-term therapy with mycophenolate mofetil, we measured levels of guanosine 5' triphosphate and adenosine 5' triphosphate in red blood cells (RBCs) of patients after heart transplantations.


METHODS
Fifty-two patients enrolled in the study were randomly assigned to one of two groups. Patients in the control group (n = 27) received cyclosporine A (INN, ciclosporin), azathioprine, and prednisone. Patients in the study group (n = 25) were switched from azathioprine to mycophenolate mofetil 3 months after the heart transplantation. Adenosine 5' triphosphate and guanosine 5' triphosphate levels were determined by means of HPLC. The activities of inosine monophosphate dehydrogenase and hypoxanthine-guanine phosphoribosyltransferase, which are responsible for guanine nucleotide formation, were measured in RBCs by radiochemical methods.


RESULTS
Adenosine 5' triphosphate levels were unchanged in patients treated with mycophenolate mofetil, whereas those of the control group who received azathioprine (from 142 +/- 26 pmol/10(6) RBCs to 165 +/- 25 pmol/10(6) RBCs; P <.001) increased. As the length of mycophenolate mofetil therapy increased, patients in the study group showed significantly elevated guanosine 5' triphosphate levels (15.6 +/- 6.1 pmol/10(6) RBCs versus 6.6 +/- 2.1 pmol/10(6) RBCs; P <.001) and a 5-fold increase in inosine monophosphate dehydrogenase activity (108.6 +/- 13.3 pmol/mg of protein per hour versus 22.5 +/- 1.7 pmol/mg of protein per hour; P <.001) compared with the control group. In addition, a slight but significant enhancement of hypoxanthine-guanine phosphoribosyltransferase activity was seen in the mycophenolate mofetil group.


CONCLUSIONS
Our studies have shown that long-term administration of mycophenolate mofetil is associated with increasing guanosine 5' triphosphate levels in RBCs as the result of an induction of inosine monophosphate dehydrogenase and hypoxanthine-guanine phosphoribosyltransferase activities in erythrocytes.
Department of Cardiothoracic Surgery, University of Vienna Medical School, and Ludwig Boltzmann Institute, Vienna, Austria.
G
G
Weigel
A
A
Griesmacher
A O
AO
Zuckermann
G
G
Laufer
M M
MM
Mueller
D000255:Adenosine Triphosphate / Q000097:blood; D001379:Azathioprine / Q000494:pharmacology / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004790:Enzyme Induction / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006160:Guanosine Triphosphate / Q000097:blood*; D016027:Heart Transplantation; D006801:Humans; D007168:IMP Dehydrogenase / Q000096:biosynthesis* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D001379:Azathioprine