Li P P, Warsh J J, Stanacev N Z
Section of Biochemical Psychiatry, Clarke Institute of Psychiatry, University of Toronto, Ontario, Canada.
Neurochem Res. 1988 Aug;13(8):789-95. doi: 10.1007/BF00971604.
The in vitro and ex vivo effects of antidepressant drugs on membrane-bound phosphatidylinositol (PI) synthetase and PI: myo-inositol exchange enzyme activities were examined. In rat brain subcellular fractions, PI synthetase occurred exclusively in the microsomes. In comparison, the activity of CDP-diglyceride independent PI:myo-inositol exchange enzyme was low (3%). Of the various CDP-diglycerides tested for the activation of PI synthetase, CDP-dipalmitin was the most active. Addition of 1 mM of desipramine, amitriptyline, imipramine, iprindole, clomipramine and mianserin in vitro significantly inhibited (30-60%) PI synthetase activity, whereas the same concentration of zimelidine and fluoxetine had no effect. At low liponucleotide concentrations, PI synthetase activity was significantly enhanced by imipramine (1 mM), whereas the enzyme activity was inhibited at higher liponucleotide concentrations (greater than 0.3 mM). In contrast, imipramine had no effect on the PI: myo-inositol exchange enzyme activity. No significant alteration in the PI synthetase activity was found following either acute (2 h) or chronic (21 d) treatment of rats with imipramine. The above results indicate that the de novo synthesis of PI is inhibited in vitro but not ex vivo by some antidepressant drugs. However, in view of the high concentration of the drugs required, the pharmacological significance of this inhibitory action with respect to their therapeutic effects is doubtful.
研究了抗抑郁药物对膜结合磷脂酰肌醇（PI）合成酶和PI：肌醇交换酶活性的体外和离体效应。在大鼠脑亚细胞组分中，PI合成酶仅存在于微粒体中。相比之下，CDP - 甘油二酯非依赖性PI：肌醇交换酶的活性较低（3%）。在测试的用于激活PI合成酶的各种CDP - 甘油二酯中，CDP - 二棕榈酸酯活性最高。在体外添加1 mM的地昔帕明、阿米替林、丙咪嗪、茚满丙二胺、氯米帕明和米安色林可显著抑制（30 - 60%）PI合成酶活性，而相同浓度的齐美利定和氟西汀则无作用。在低核苷酸浓度下，丙咪嗪（1 mM）可显著增强PI合成酶活性，而在较高核苷酸浓度（大于0.3 mM）时酶活性受到抑制。相比之下，丙咪嗪对PI：肌醇交换酶活性无影响。用丙咪嗪对大鼠进行急性（2小时）或慢性（21天）处理后，未发现PI合成酶活性有显著改变。上述结果表明，一些抗抑郁药物在体外可抑制PI的从头合成，但在离体情况下则不然。然而，鉴于所需药物浓度较高，这种抑制作用对其治疗效果的药理学意义值得怀疑。
