Allison A C, Eugui E M
Dawa Incorporated, Belmont, CA 94002, USA.
Clin Transplant. 1996 Feb;10(1 Pt 2):77-84.
Mycophenolate mofetil (MMF) is a novel immunosuppressive drug that shows promise in preventing the rejection of organ allografts and in the treatment of ongoing rejection. Orally administered MMF is hydrolyzed by esterases in the intestine and blood to release mycophenolic acid (MPA), a potent, selective, noncompetitive inhibitor of the type 2 isoform of inosine monophosphate dehydroxygenase (IMPDH) expressed in activated human T and B lymphocytes. By inhibiting IMPDH, MPA depletes the pool of dGTP required for DNA synthesis. MPA has a more potent cytostatic effect on lymphocytes than on other cell types, and this is the principal mechanism by which immunosuppressive activity is exerted. MPA also depletes pools of GTP in human lymphocytes and monocytes, thereby inhibiting the synthesis of fucose- and mannose-containing saccharide components of membrane glycoproteins. These are recognized by the family of adhesion molecules termed selectins. By this mechanism, MPA could decrease the recruitment of lymphocytes and monocytes into sites of graft rejection. In addition to preventing allograft rejection, MMF suppresses graft-versus-host reactions in lethal and nonlethal murine models. MMF inhibits primary antibody responses more efficiently than secondary responses. MPA inhibits the proliferation of human B lymphocytes transformed by Epstein-Barr virus and is not mutagenic. Clinically attainable concentrations of MPA suppress the proliferation of human arterial smooth muscle cells. These two properties of MPA may decrease the risk of lymphoma development and proliferative arteriopathy in long-term recipients of MMF.
霉酚酸酯（MMF）是一种新型免疫抑制药物，在预防器官移植排斥反应及治疗正在发生的排斥反应方面显示出前景。口服的MMF在肠道和血液中被酯酶水解，释放出霉酚酸（MPA），MPA是一种强效、选择性、非竞争性的肌苷单磷酸脱氢酶（IMPDH）2型同工酶抑制剂，该同工酶在活化的人T和B淋巴细胞中表达。通过抑制IMPDH，MPA耗尽DNA合成所需的dGTP池。MPA对淋巴细胞的细胞生长抑制作用比对其他细胞类型更强，这是发挥免疫抑制活性的主要机制。MPA还耗尽人淋巴细胞和单核细胞中的GTP池，从而抑制膜糖蛋白中含岩藻糖和甘露糖的糖成分的合成。这些成分可被称为选择素的黏附分子家族识别。通过这种机制，MPA可减少淋巴细胞和单核细胞募集到移植排斥部位。除了预防移植排斥反应外，MMF在致死和非致死性小鼠模型中还能抑制移植物抗宿主反应。MMF抑制初次抗体反应比二次反应更有效。MPA抑制由爱泼斯坦-巴尔病毒转化的人B淋巴细胞的增殖，且无致突变性。临床可达到的MPA浓度可抑制人动脉平滑肌细胞的增殖。MPA的这两个特性可能会降低长期接受MMF治疗的患者发生淋巴瘤和增殖性动脉病的风险。
