Inosine Monophosphate Dehydrogenase: The Molecular Target of Mycophenolate
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AbstractMycophenolic acid (MPA) is frequently included in immunosuppressive drug regimens to prevent organ rejection after transplantation. The immunosuppressive effects of mycophenolate are mediated through inhibition of the enzyme inosine monophosphate dehydrogenase (IMPDH), thus suppressing the proliferation of lymphocytes. The activity of IMPDH is constituted by two separate isoenzymes, type 1 and 2, which are encoded by the IMPDH1 and IMPDH2 genes, respectively. Measurement of IMPDH activity is investigated as a pharmacodynamic approach for individualization of MPA therapy to improve the clinical outcome after transplantation.
The aims of the thesis were to characterize the two IMPDH isoenzymes during exposure to MPA. An assay was developed and validated for determination of IMPDH1 and IMPDH2 gene expression in blood cells. The assay was further utilized for analysis in clinical samples from transplanted patients and healthy individuals to explore the regulation of IMPDH 1 and 2 in blood cells during in vivo exposure to MPA.
The studies demonstrate that the gene expression of both IMPDH isoforms, as well as IMPDH activity, is influenced by factors like corticosteroid and mycophenolate treatment and the activation status of lymphocytes. The IMPDH regulation differs between isoforms and cell types, and changes with time since transplantation. A significant association between the IMPDH2 expression in CD4+ cells before transplantation and the risk of rejection supports the potential of individualizing MPA therapy based on IMPDH measurements. However, the significant impact of corticosteroids and MPA and changes over time should be considered when interpreting IMPDH measurements.
In conclusion, the results provide a better understanding of the IMPDH regulation during MPA therapy. This knowledge is important considering the potential for individualization of MPA dosing based on IMPDH measurements.
List of Papers
(1-3 are removed due to publisher restrictions)
I. Bremer S, Rootwelt H, Bergan S. Real-time PCR determination of IMPDH1 and IMPDH2 expression in blood cells. Clinical Chemistry. 2007; 53 (6): 1023-1029. DOI: 10.1373/clinchem.2006.081968
II. Bremer S, Mandla R, Vethe NT, Rasmussen I, Rootwelt H, Line PD, Midtvedt K, Bergan S. Expression of IMPDH1 and IMPDH2 after transplantation and nitiation of immunosuppression. Transplantation. 2008; 85 (1): 55-61. DOI: 10.1097/01.tp.0000296854.68123.03
III. Bremer S, Vethe NT, Rootwelt H, Bergan S. Expression of IMPDH1 is regulated in response to mycophenolate concentration. International Immunopharmacology. 2009; 9 (2): 173-180. DOI: 10.1016/j.intimp.2008.10.017
IV. Bremer S, Vethe NT, Rootwelt H, Jørgensen PF, Stenstrøm J, Holdaas H, Midtvedt K, Bergan S. Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients. Submitted. Published: Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study. Bremer S, Vethe NT, Rootwelt H, Jorgensen PF, Stenstrom J, Holdaas H, Midtvedt K, Bergan S. JOURNAL OF TRANSLATIONAL MEDICINE. 2009; vol 7, article number: 64 DOI: 10.1186/1479-5876-7-64