Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics
Regional and cellular expression of CYP2D6 in human brain: higher levels in alcoholics
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DOI：
10.1046/j.1471-4159.2002.01069.x
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发表时间：
2002-09-01
影响因子：
4.7
通讯作者：
Tyndale, RF
中科院分区：
文献类型：
--
作者：
Miksys, S;Rao, Y;Tyndale, RF
细胞色素P450（CYP 2D 6）在肝脏、脑和其他肝外组织中表达，在这些组织中代谢一系列中枢作用药物和毒素。由于乙醇可以诱导大鼠脑中的CYP 2D，我们假设CYP 2D 6在人类酗酒者的脑中表达更高。采用RT-PCR、Southern印迹、狭缝印迹、免疫印迹和免疫细胞化学等方法检测了CYP 2D 6 mRNA和蛋白的区域和细胞表达。在13个脑区的平均mRNA和CYP 2D 6蛋白水平之间发现了显着的相关性。酗酒者（n = 8）的13个脑区的表达高于非酗酒者（n = 5）（anovap < 0.0001）。海马CA 1 -3区锥体细胞和齿状回颗粒神经元中有表达。在小脑中，这局限于浦肯野细胞及其树突。这两个大脑区域，以及这些相同的细胞类型，都被认为容易受到酒精损伤。对于1例弱代谢者（CYP 2D 6 * 4/*4），未检出CYP 2D 6蛋白，证实了所用抗体的特异性。这些数据表明，在酗酒者中，脑CYP 2D 6表达升高可能有助于改变对中枢作用药物的敏感性，并介导酒精的神经毒性和行为效应。
Cytochrome P450 (CYP) 2D6 is expressed in liver, brain and other extrahepatic tissues where it metabolizes a range of centrally acting drugs and toxins. As ethanol can induce CYP2D in rat brain, we hypothesized that CYP2D6 expression is higher in brains of human alcoholics. We examined regional and cellular expression of CYP2D6 mRNA and protein by RT-PCR, Southern blotting, slot blotting, immunoblotting and immunocytochemistry. A significant correlation was found between mean mRNA and CYP2D6 protein levels across 13 brain regions. Higher expression was detected in 13 brain regions of alcoholics (n = 8) compared to nonalcoholics (n = 5) (anovap < 0.0001). In hippocampus this was localized in CA1-3 pyramidal cells and dentate gyrus granular neurons. In cerebellum this was localized in Purkinje cells and their dendrites. Both of these brain regions, and these same cell-types, are known to be susceptible to alcohol damage. For one case, a poor metabolizer (CYP2D6* 4/*4), there was no detectable CYP2D6 protein, confirming the specificity of the antibody used. These data suggest that in alcoholics elevated brain CYP2D6 expression may contribute to altered sensitivity to centrally acting drugs and to the mediation of neurotoxic and behavioral effects of alcohol.