Voirol P, Jonzier-Perey M, Porchet F, Reymond M J, Janzer R C, Bouras C, Strobel H W, Kosel M, Eap C B, Baumann P
Unité de Biochimie et Psychopharmacologie Clinique, Département Universitaire de Psychiatrie Adulte, CH-1008 Prilly, Lausanne, Switzerland.
Brain Res. 2000 Feb 14;855(2):235-43. doi: 10.1016/s0006-8993(99)02354-9.
The role of cytochrome P450 in the metabolism of dextromethorphan, amitriptyline, midazolam, S-mephenytoin, citalopram, fluoxetine and sertraline was investigated in rat and human brain microsomes. Depending on the parameters, the limit of quantification using gas chromatography-mass spectrometry methods was between 1.6 and 20 pmol per incubation, which generally contained 1500 microg protein. Amitriptyline was shown to be demethylated to nortriptyline by both rat and human microsomes. Inhibition studies using ketoconazole, furafylline, sulfaphenazole, omeprazole and quinidine suggested that CYP3A4 is the isoform responsible for this reaction whereas CYP1A2, CYP2C9, CYP2C19 and CYP2D6 do not seem to be involved. This result was confirmed by using a monoclonal antibody against CYP3A4. Dextromethorphan was metabolized to dextrorphan in rat brain microsomes and was inhibited by quinidine and by a polyclonal antibody against CYP2D6. Only the addition of exogenous reductase allowed the measurement of this activity in human brain microsomes. Metabolites of the other substrates could not be detected, possibly due to an insufficiently sensitive method. It is concluded that cytochrome P450 activity in the brain is very low, but that psychotropic drugs could undergo a local cerebral metabolism which could have pharmacological and/or toxicological consequences.
在大鼠和人脑微粒体中研究了细胞色素P450在右美沙芬、阿米替林、咪达唑仑、S-美芬妥因、西酞普兰、氟西汀和舍曲林代谢中的作用。根据参数，使用气相色谱-质谱法的定量限为每次孵育1.6至20皮摩尔，每次孵育通常含有1500微克蛋白质。大鼠和人脑微粒体均显示可将阿米替林脱甲基化为去甲替林。使用酮康唑、呋拉茶碱、磺胺苯唑、奥美拉唑和奎尼丁的抑制研究表明，CYP3A4是负责该反应的同工酶，而CYP1A2、CYP2C9、CYP2C19和CYP2D6似乎不参与其中。使用抗CYP3A4单克隆抗体证实了这一结果。右美沙芬在大鼠脑微粒体中代谢为右啡烷，并受到奎尼丁和抗CYP2D6多克隆抗体的抑制。只有添加外源性还原酶才能在人脑微粒体中测量该活性。其他底物的代谢产物无法检测到，可能是由于方法不够灵敏。结论是，脑中细胞色素P450活性非常低，但精神药物可能会发生局部脑代谢，这可能会产生药理学和/或毒理学后果。
