Stet E H, De Abreu R A, Bökkerink J P, Lambooy L H, Vogels-Mentink T M, Keizer-Garritsen J J, Trijbels F J
Department of Paediatrics, St Radboud University Hospital of Nijmegen, The Netherlands.
Ann Clin Biochem. 1994 Mar;31 ( Pt 2):174-80. doi: 10.1177/000456329403100211.
The effects of inhibition of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide de novo synthesis, on cell growth, cell viability, endogenous nucleotide concentrations and concentrations of extracellular nucleosides and bases were studied in Molt F4 human malignant lymphoblasts. Mycophenolic acid (MPA) was used as a specific inhibitor of the enzyme activity. IMPDH activity was maximally inhibited with 0.5 microM MPA. After a 2 h exposure of the cells to 0.5 microM MPA, guanine nucleotides were depleted to approximately 50% of control values, whereas 5-phosphoribosyl-1-pyrophosphate levels increased to approximately 200%. Under these conditions, cytotoxicity became obvious after 24 h. Depletion of guanine nucleotides and cytotoxicity were prevented by addition of guanosine to MPA treatment. Daily supplements of guanosine were required to prevent MPA cytotoxicity during the entire incubation period of 72 h. We conclude that depletion of guanine nucleotides, induced by treatment with MPA, induces a severe and rapid cytotoxicity in Molt F4 cells.
在Molt F4人恶性淋巴母细胞中，研究了抑制鸟嘌呤核苷酸从头合成的限速酶肌苷单磷酸脱氢酶（IMPDH）对细胞生长、细胞活力、内源性核苷酸浓度以及细胞外核苷和碱基浓度的影响。霉酚酸（MPA）用作该酶活性的特异性抑制剂。0.5微摩尔/升的MPA可最大程度地抑制IMPDH活性。将细胞暴露于0.5微摩尔/升的MPA 2小时后，鸟嘌呤核苷酸减少至对照值的约50%，而5-磷酸核糖-1-焦磷酸水平增加至约200%。在这些条件下，24小时后细胞毒性变得明显。通过在MPA处理中添加鸟苷可防止鸟嘌呤核苷酸的消耗和细胞毒性。在整个72小时的孵育期内，需要每日补充鸟苷以防止MPA的细胞毒性。我们得出结论，MPA处理诱导的鸟嘌呤核苷酸耗竭在Molt F4细胞中诱导了严重且快速的细胞毒性。
