title: Mycophenolate mofetil treatment following renal transplantation decreases GTP concentrations in mononuclear leucocytes.
abstract: MMF (mycophenolate mofetil) has been proven to provide an effective immunosuppression by non-competitive selective reversible inhibition of IMPDH (inosine monophosphate dehydrogenase), the enzyme playing a crucial role in GTP biosynthesis. However, the exact metabolic changes induced by inhibition of IMPDH in target cells of the immune system have been the subject of recent debate. The aim of the present study was to evaluate whether MMF treatment produced sustained changes in the guanosine nucleotide pool of MNLs (mononuclear leucocytes) in vivo. Sixty-two renal failure patients were divided into three groups: chronic renal failure patients undergoing haemodialysis (CRF-HD; n=20) and two groups of patients after renal transplantation, the first on AZA (azathioprine; TN-AZA; n=23) and the second treated with MMF (TN-MMF; n=19). In addition, MNLs from 25 healthy subjects were analysed as controls. Anion-exchange HPLC was used to quantify purine and pyrimidine nucleotides in MNLs. We report a significant decrease in GTP and the total MNL guanine nucleotide pool in the TN-MMF group (P<0.05) compared with control, CRF-HD and TN-AZA groups, although no significant differences were found between any of the other groups. Adenine nucleotide concentrations in MNLs were decreased in the TN-AZA group, but not in the TN-MMF group compared with the CRF-HD group and controls. There were no differences in CTP concentrations, but UTP concentrations were decreased in the CRF-HD, TN-AZA and TN-MMF groups compared with controls. MMF caused a significant and sustained decrease in the guanine nucleotide pool in MNLs from renal transplant recipients. This decrease contrasts with the elevation in GTP reported in erythrocytes of MMF-treated patients.
authors.affiliation: Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, Debinki 7 Str., 80-211 Gdansk, Poland. pjagod@amg.gda.pl
authors.forename: Piotr
authors.initials: P
authors.lastname: Jagodzinski
authors.forename: Slawomir
authors.initials: S
authors.lastname: Lizakowski
authors.forename: Ryszard T
authors.initials: RT
authors.lastname: Smolenski
authors.forename: Ewa M
authors.initials: EM
authors.lastname: Slominska
authors.forename: David
authors.initials: D
authors.lastname: Goldsmith
authors.forename: H Anne
authors.initials: HA
authors.lastname: Simmonds
authors.forename: Boleslaw
authors.initials: B
authors.lastname: Rutkowski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000494:pharmacology; D002648:Child; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006160:Guanosine Triphosphate / Q000097:blood*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000097:blood; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011184:Postoperative Period; D011685:Purine Nucleotides / Q000097:blood; D011742:Pyrimidine Nucleotides / Q000097:blood
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D001379:Azathioprine