Faraci W S, Zorn S H, Bakker A V, Jackson E, Pratt K
Central Research Division, Pfizer Inc., Groton, CT 06340.
Biochem J. 1993 Apr 15;291 ( Pt 2)(Pt 2):369-74. doi: 10.1042/bj2910369.
Despite limiting side-effects, lithium is the drug of choice for the treatment of bipolar depression. Its action may be due, in part, to its ability to dampen phosphatidylinositol turnover by inhibiting myo-inositol monophosphatase. Beryllium has been identified as a potent inhibitor of partially purified myo-inositol monophosphatase isolated from rat brain (Ki = 150 nM), bovine brain (Ki = 35 nM), and from the human neuroblastoma cell line SK-N-SH (Ki = 85 nM). It is over three orders of magnitude more potent than LiCl (Ki = 0.5-1.2 mM). Kinetic analysis reveals that beryllium is a competitive inhibitor of myo-inositol monophosphatase, in contrast with lithium which is an uncompetitive inhibitor. Inhibition of exogenous [3H]inositol phosphate hydrolysis by beryllium (IC50 = 250-300 nM) was observed to the same maximal extent as that seen with lithium in permeabilized SK-N-SH cells, reflecting inhibition of cellular myo-inositol monophosphatase. However, in contrast with that observed with lithium, agonist-induced accumulation of inositol phosphate was not observed with beryllium in permeabilized and non-permeabilized SK-N-SH cells and in rat brain slices. Similar results were obtained in permeabilized SK-N-SH cells when GTP-gamma-S was used as an alternative stimulator of inositol phosphate accumulation. The disparity in the actions of beryllium and lithium suggest that either (1) selective inhibition of myo-inositol monophosphatase does not completely explain the action of lithium on the phosphatidylinositol cycle, or (2) that uncompetitive inhibition of myo-inositol monophosphatase is a necessary requirement to observe functional lithium mimetic activity.
尽管锂的副作用有限，但它仍是治疗双相抑郁症的首选药物。其作用可能部分归因于它通过抑制肌醇单磷酸酶来抑制磷脂酰肌醇周转的能力。铍已被确定为从大鼠脑（Ki = 150 nM）、牛脑（Ki = 35 nM）以及人神经母细胞瘤细胞系SK-N-SH（Ki = 85 nM）中分离出的部分纯化的肌醇单磷酸酶的强效抑制剂。它的效力比LiCl（Ki = 0.5 - 1.2 mM）高三个数量级以上。动力学分析表明，铍是肌醇单磷酸酶的竞争性抑制剂，而锂是反竞争性抑制剂。在通透的SK-N-SH细胞中，观察到铍对外源性[3H]肌醇磷酸水解的抑制作用（IC50 = 250 - 300 nM）与锂的抑制作用达到相同的最大程度，这反映了对细胞内肌醇单磷酸酶的抑制。然而，与锂不同的是，在通透和未通透的SK-N-SH细胞以及大鼠脑切片中，铍并未观察到激动剂诱导的肌醇磷酸积累。当使用GTP-γ-S作为肌醇磷酸积累的替代刺激剂时，在通透的SK-N-SH细胞中也得到了类似的结果。铍和锂作用的差异表明，要么（1）对肌醇单磷酸酶的选择性抑制并不能完全解释锂对磷脂酰肌醇循环的作用，要么（2）对肌醇单磷酸酶的反竞争性抑制是观察到功能性锂模拟活性的必要条件。
