IMP-dehydrogenase inhibition in human lymphocytes and lymphoblasts by mycophenolic acid and mycophenolic acid glucuronide.
Inosine 5'-monophosphate dehydrogenase (IMP-DH) activities were measured in human lymphocytes (exhibiting type I IMP-DH activity) and human lymphoblasts (exhibiting type II IMP-DH activity) in the presence of various amounts of mycophenolic acid (MPA) (0-20 mumol/L) and MPA glucuronide (MPAG) (0-200 mumol/L). Moreover, the influences of human serum albumin (HSA) and human plasma on the MPA- and MPAG-mediated effects were investigated. In the presence of water, 2.5 mumol/L MPA decreased the IMP-DH activity measured in lymphocytes by 60%, whereas in lymphoblasts a 80% inhibition was detectable. In the presence of > or = 10 mumol/L MPA, lymphocytic as well as lymphoblastic IMP-DH activities were reduced in a similar manner. The concentration of MPAG required for 50% inhibition was for both cell types > 25 mumol/L and < 50 mumol/L, respectively. MPAG (200 mumol/L) reduced lymphocytic as well as lymphoblastic IMP-DH activity by approximately 80%. With 100 g/L HSA or human plasma as diluent, the inhibitory effects of MPA and MPAG were significantly (P < 0.05) diminished, whereas HSA concentrations < or = 25 g/L only slightly influenced the inhibition of IMP-DH activity by MPA and MPAG. In summary, it can be clearly demonstrated that not only MPA but also MPAG contributes to the inhibition of both IMP-DH isoenzymes, which might be relevant for the immunosuppressive properties of mycophenolate mofetil in transplant patients.
Griesmacher
A
A
Ludwig-Boltzmann-Institute for Cardiothoracic Surgical Research, Kaiser-Franz-Josef-Hospital, Vienna, Austria.
Weigel
G
G
Seebacher
G
G
Müller
M M
MM
D001798:Blood Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008214:Lymphocytes / Q000201:enzymology*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D012709:Serum Albumin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014867:Water
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007527:Isoenzymes; D012709:Serum Albumin; D014867:Water; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid