Constitutive expression and localization of the major drug metabolizing enzyme, cytochrome P4502D in human brain
Constitutive expression and localization of the major drug metabolizing enzyme, cytochrome P4502D in human brain
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DOI：
10.1016/s0169-328x(02)00177-8
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发表时间：
2002-06-30
期刊：
影响因子：
--
通讯作者：
Ravindranath, V
中科院分区：
文献类型：
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作者：
Chinta, SJ;Pai, HV;Ravindranath, V
细胞色素P4502D6是细胞色素P450的重要亚型，参与多种精神活性药物在肝脏中的代谢。从数量上讲，肝脏是主要的药物代谢器官，然而药物在大脑中的代谢可以调节作用部位的精神活性药物的药理和药效作用，并解释了患者群体中常见的一些变化。采用逆转录-聚合酶链式反应、Northern杂交和免疫印迹等方法检测了人脑组织细胞色素P450的含量，并用原位杂交和免疫组织化学方法对其进行了定位。在大脑皮层神经元、小脑浦肯野层和颗粒细胞层、中脑网状结构神经元以及海马区CA1、CA2和CA3区锥体神经元均有CYP2D mRNA的组成性表达。免疫印迹研究表明，细胞色素P4502D蛋白存在于人脑的皮质、小脑、中脑、纹状体和丘脑。免疫组织化学定位显示，细胞色素P4502D不仅存在于神经元胞体，而且存在于浦肯野和皮质神经元的树突中。这些研究证实了细胞色素P4502D在人脑的神经细胞群中的结构性表达，表明它可能在精神活性药物在其作用部位或附近的人脑神经元中的代谢中发挥作用。(C)2002年爱思唯尔科学公司。版权所有。
Cytochrome P4502D6, an important isoform of cytochrome P450, mediates the metabolism of several psychoactive drugs in liver. Quantitatively, liver is the major drug metabolizing organ, however metabolism of drugs in brain could modulate pharmacological and pharmacodynamic effects of psychoactive drugs at their site of action and explain some of the variation typically seen in patient population. We have measured cytochrome P450 content and examined constitutive expression of CYP2D mRNA and protein in human brain regions by reverse transcription polymerase chain reaction, Northern and immunoblotting and localized it by in situ hybridization and immunohistochemistry. CYP2D mRNA was expressed constitutively in neurons of cerebral cortex, Purkinje and granule cell layers of cerebellum, reticular neurons of midbrain and pyramidal neurons of CA1, CA2 and CA3 subfields of hippocampus. Immunoblot studies demonstrated the presence of cytochrome P4502D protein in cortex, cerebellum, midbrain, striatum and thalamus of human brain. Immunohistochemical localization showed the predominant presence of cytochrome P4502D not only in neuronal soma but also in dendrites of Purkinje and cortical neurons. These studies demonstrate constitutive expression of cytochrome P4502D in neuronal cell population in human brain, indicating its possible role in metabolism of psychoactive drugs directly at or near their site of action, in neurons, in human brain. (C) 2002 Elsevier Science BY. All rights reserved.