Activation of the purine salvage pathway in mononuclear cells of cardiac recipients treated with mycophenolate mofetil.
BACKGROUND
The objective of this study was to investigate purine nucleotide metabolism in peripheral blood mononuclear cells (PBMC) of cardiac transplant recipients switched from azathioprine to mycophenolate mofetil (MMF).


METHODS
Concentrations of guanosine 5'triphosphate (GTP) and adenosine 5'triphosphate (ATP), the activities of inosine monophosphate dehydrogenase (IMPDH), guanine phosphoribosyltransferase (GPRT), and hypoxanthine phosphoribosyltransferase (HPRT) were determined in PBMC of 27 cardiac transplant recipients before switch to MMF and 3, 6, and 12 months thereafter.


RESULTS
There was no difference in the activities of IMPDH and salvage pathway enzymes GPRT and HRPT as well as in intracellular GTP and ATP concentrations between the patients before switch to MMF and healthy controls. The GTP and ATP concentrations in PBMC of cardiac recipients did not change during the entire observation period. Although the MPA trough level remained similar, IMPDH activity declined from 897 to 316 pmol/10(6)PBMC/h 3 months after MMF onset, was almost completely inhibited after 6 months, and partially restored to 143 pmol/10(6)PBMC/h 12 months after switch to MMF. In contrast, GPRT activity increased after 3, 6, and 12 months of MMF therapy and HPRT activity 3 and 6 months after switch to MMF.


CONCLUSIONS
We demonstrated for the first time an induction of salvage pathway enzyme activities in PBMC under MMF therapy. This probably accounts for the maintenance of intracellular purine nucleotide pools and prevents the GTP depletion.
Devyatko
Elena
E
Department of General Surgery and Transplantation, University Clinic of Surgery, Medical University Vienna, Vienna, Austria. yelena.devyatko@meduniwien.ac.at
Zuckermann
Andreas
A
Bohdjalian
Arthur
A
Roedler
Suzanne
S
Dunkler
Daniela
D
Grimm
Michael
M
Weigel
Guenter
G
D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage; D004789:Enzyme Activation; D005260:Female; D006160:Guanosine Triphosphate / Q000032:analysis / Q000378:metabolism; D016027:Heart Transplantation; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism*; D007168:IMP Dehydrogenase / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011685:Purine Nucleotides / Q000032:analysis / Q000378:metabolism*
D007166:Immunosuppressive Agents; D011685:Purine Nucleotides; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D007168:IMP Dehydrogenase; D007041:Hypoxanthine Phosphoribosyltransferase; D009173:Mycophenolic Acid; D001379:Azathioprine