An exploratory study on pharmacogenetics of inosine-monophosphate dehydrogenase II in peripheral mononuclear cells from liver-transplant recipients.
Mycophenolate mofetil (MMF) is an immunosuppressant used for the prophylaxis of rejection in renal, pancreas, and liver transplantation. It inhibits the inducible isoform of the enzyme inosine-monophosphate dehydrogenase (IMPDH II) via its active metabolite mycophenolic acid (MPA). IMPDH II is necessary for de novo purine synthesis in activated lymphocytes. The aims of the present study were to evaluate the feasibility of a real-time polymerase chain reaction (PCR) quantitative assessment of IMPDH II gene expression in liver transplant recipients as well as to provide a preliminary evaluation of possible correlations with drug tolerability. RNA was extracted from peripheral blood mononuclear cells of liver recipients after at least 6 months of MMF administration. IMPDH II gene expression was assessed using quantitative, real-time PCR and normalized using glyceraldheyde-3-phosphate dehydrogenase (GAPDH). Finally, adverse events associated with MMF administration were recorded. Real-time PCR quantitation of IMPDH II gene expression was reliable, sensitive, and specific. The intrapatient variability for both IMPDH II and GAPDH assays was lower than 0.6% in all patients. The results demonstrated a wide interpatient variability, with the mean value +/- standard deviation of 0.949 +/- 0.525 (95% confidence interval, 0.669-1.229) and a median value of 0.797. Patients with treatment-related toxicities displayed a trend to a higher level of IMPDH II expression than those without toxicity (mean, 1.126 vs 0.771). In conclusion, pharmacogenetic analysis of IMPDH II may represent a novel approach to MMF therapeutic monitoring.
Vannozzi
F
F
Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, 56126 Pisa, Italy.
Filipponi
F
F
Di Paolo
A
A
Danesi
R
R
Urbani
L
L
Bocci
G
G
Catalano
G
G
De Simone
P
P
Mosca
F
F
Del Tacca
M
M
D000328:Adult; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007168:IMP Dehydrogenase / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016031:Liver Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D010597:Pharmacogenetics / Q000379:methods; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; C501687:IMPDH2 protein, human; D009173:Mycophenolic Acid