BACKGROUND: Clinical studies suggest that the immunosuppressant mycophenolate mofetil is associated with anemia. However, the mechanism for this is not known. Here, we studied the effect of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, on erythropoiesis in vitro. METHODS: Both UT-7 cells and primary murine bone marrow cells were studied. Cells were initially treated with erythropoietin and MPA and proliferation and caspase-3 assays were performed. The effect of guanosine-5'-triphosphate, guanosine, and caspase inhibitors was also investigated. RESULTS: MPA was found to decrease the proliferation of UT-7 cells and erythropoiesis in murine bone marrow cells. This inhibition was associated with an increase in caspase-3 activity in the UT-7 cells. Inhibition was reversed in UT-7 cells and in murine bone marrow by guanosine, but not by caspase inhibitors. The apoptosis induced by MPA was also reversed by guanosine. UT-7 cells treated with MPA showed a decreased inosine-5'-monophosphate dehydrogenase activity. CONCLUSION: These results suggest that MPA inhibits inosine-5'-monophosphate dehydrogenase activity in erythroid cells and that this is a likely mechanism of action of anemia in MPA-treated patients.
BACKGROUND: Clinical studies suggest that the immunosuppressant mycophenolate mofetil is associated with anemia. However, the mechanism for this is not known. Here, we studied the effect of mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, on erythropoiesis in vitro. METHODS: Both UT-7 cells and primary murine bone marrow cells were studied. Cells were initially treated with erythropoietin and MPA and proliferation and caspase-3 assays were performed. The effect of guanosine-5'-triphosphate, guanosine, and caspase inhibitors was also investigated. RESULTS:MPA was found to decrease the proliferation of UT-7 cells and erythropoiesis in murine bone marrow cells. This inhibition was associated with an increase in caspase-3 activity in the UT-7 cells. Inhibition was reversed in UT-7 cells and in murine bone marrow by guanosine, but not by caspase inhibitors. The apoptosis induced by MPA was also reversed by guanosine. UT-7 cells treated with MPA showed a decreased inosine-5'-monophosphate dehydrogenase activity. CONCLUSION: These results suggest that MPA inhibits inosine-5'-monophosphate dehydrogenase activity in erythroid cells and that this is a likely mechanism of action of anemia in MPA-treated patients.
Authors: Azrin N Abd Rahman; Susan E Tett; Halim A Abdul Gafor; Brett C McWhinney; Christine E Staatz Journal: Br J Clin Pharmacol Date: 2015-07-02 Impact factor: 4.335