Effect of psychotropic drugs on the 21-hydroxylation of neurosteroids, progesterone and allopregnanolone, catalyzed by rat CYP2D4 and human CYP2D6 in the brain.
Effect of psychotropic drugs on the 21-hydroxylation of neurosteroids, progesterone and allopregnanolone, catalyzed by rat CYP2D4 and human CYP2D6 in the brain.
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DOI：
10.1248/bpb.31.348
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发表时间：
2008-03
影响因子：
2
通讯作者：
T. Niwa;K. Okada;T. Hiroi;S. Imaoka;S. Narimatsu;Y. Funae
中科院分区：
文献类型：
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作者：
T. Niwa;K. Okada;T. Hiroi;S. Imaoka;S. Narimatsu;Y. Funae
我们确定了精神药物对细胞色素P450 2D（CYP 2D）介导的孕酮（PROG）和别孕烯醇酮（ALLO）的21-羟基化的影响，目的是澄清神经甾体水平是否受大脑中精神药物的影响。在典型精神药物氟西汀、丙咪嗪、地昔帕明、马吲哚和GBR 12909存在下，将PROG或ALLO与大鼠CYP 2D 4或人CYP 2D 6孵育，并分别通过高效液相色谱和液相色谱-串联质谱法测定PROG和ALLO的21-羟基化代谢产物。氟西汀竞争性抑制CYP 2D 4介导的PROG 21-羟基化，并增加CYP 2D 6介导的PROG 21-羟基化的Km和Vmax值。此外，氟西汀竞争性抑制由CYP 2D 4和CYP 2D 6介导的ALLO 21-羟基化。丙咪嗪、地昔帕明、马吲哚和GBR 12909竞争性抑制CYP 2D 4和/或CYP 2D 6介导的PROG 21-羟基化，所有精神药物均抑制CYP 2D 4和/或CYP 2D 6介导的ALLO 21-羟基化。丙咪嗪，地昔帕明，马吲哚对21-羟基化的PROG和ALLO的CYP 2D 6的抑制常数（Ki值）低于CYP 2D 4。这些结果表明，包括氟西汀在内的精神药物会影响大脑中神经类固醇（例如PROG和ALLO）的代谢，这表明神经类固醇水平的调节受到抑制大脑CYP 2D亚型的中枢神经系统活性药物的调节。
We determined the effects of psychotropic drugs on the cytochrome P450 2D (CYP2D)-mediated 21-hydroxylation of progesterone (PROG) and allopregnanolone (ALLO) with the goal of clarifying whether neurosteroid levels are affected by psychotropic drugs in the brain. PROG or ALLO was incubated with rat CYP2D4 or human CYP2D6 in the presence of typical psychotropic drugs, fluoxetine, imipramine, desipramine, mazindol, and GBR12909, and the 21-hydroxylated metabolites of PROG and ALLO were determined by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry, respectively. Fluoxetine competitively inhibited CYP2D4-mediated PROG 21-hydroxylation and increased both Km and Vmax values of CYP2D6-mediated PROG 21-hydroxylation. In addition, fluoxetine competitively inhibited ALLO 21-hydroxylation mediated by CYP2D4 and CYP2D6. Imipramine, desipramine, mazindol, and GBR12909 competitively inhibited PROG 21-hydroxylation mediated by CYP2D4 and/or CYP2D6, and all psychotropic drugs inhibited ALLO 21-hydroxylation mediated by CYP2D4 and/or CYP2D6. The inhibition constants (Ki values) of imipramine, desipramine, and mazindol against the 21-hydroxylation of PROG and ALLO by CYP2D6 were lower than those by CYP2D4. These results indicate that psychotropic drugs including fluoxetine affected the metabolism of neurosteroids, such as PROG and ALLO in the brain, suggesting that the regulation of the neurosteroid levels is modified by central nervous system-active drugs that inhibit brain CYP2D isoforms.