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Human Brain CYP P450s and Psychoactive Drug Metabolism

人脑 CYP P450 与精神活性药物代谢

基本信息

批准号：
7263196
负责人：
HENRY W STROBEL
金额：
$ 38.26万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7263196
关键词：
Address Affect Age Alprazolam Amino Acids Amphetamines Analgesics Antidepressive Agents Antipsychotic Agents Autopsy Base Pairing Benzphetamine Binding Biological Availability Brain Brain Diseases Brain region CYP2D6 gene CYP3A4 gene Cells Chlorpromazine Code Codeine Cytochrome P450 Detection Disease Distal Docking Drug effect disorder Effectiveness Enzymes Escherichia coli Ethnic Origin Ethylmorphine Fluoxetine Gender Haloperidol Homology Modeling Human Human Identifications Imipramine In Situ Hybridization Liver Localized Messenger RNA Metabolism Methylphenidate Microsomes Modification Morphine Numbers Organ Parents Patients Pharmaceutical Preparations Polymerase Chain Reaction Population Process Protein Isoforms Proteins Psychotropic Drugs RNA Range Rattus Recombinant Proteins Relative (related person)Reverse Transcriptase Polymerase Chain Reaction Role Screening procedure Site Small Intestines System Techniques Therapeutic Therapeutic Effect Time Variant Yeasts absorption brain tissue cDNA Library drug metabolism expression cloning insight norcodeine novel response selective expression therapeutic target

项目摘要

DESCRIPTION (provided by applicant): A number of cytochromes P450 expressed in liver have also been shown to be expressed in human and rat brain using techniques of in situ hybridization and immunohistochemical detection. Moreover, using human and rat brain microsomes, the P450-dependent metabolism of drugs and stercids has been demonstrated showing that brain cytochromes P450 are catalytically active. Recently a unique CYP2D form has been identified as expressed only in the brain of 9 out of 20 cadaveric donors examined. This CYP2D form, cloned and expressed in Neuro 2A cells, has a unique catalytic activity, converting codeine exclusively to morphine, thereby demonstrating not only unique brain specific localization, but also, a specific functional activity. This proposal will focus on the definition of expression of this and other P450 forms uniquely expressed in human brain. This objective will be accomplished by defining the regional distribution of such forms in brain as a function of gender, age and ethnicity as well as by definition of the catalytic capacities of these expressed purified P450s towards a panel of neuroactive psychoactive drugs clinically utilized to treat brain disorders. The drug panel will include the antidepressants fluoxetine and imipramine the neuroleptics chlorpromazine and haloperidol, the antianxiety drug alprazolam, the antihyperactivity drug methylphenidate, the analgesic ethylmorphine and the amphetamine benzphetamine. We will define the catalytic activities of these drugs in human brain microsomes. We will define the regional expression of these novel forms using QRTPCR with RNA isolated from brain regions as well as by in situ hybridization techniques. We will express the cloned unique forms in heterologous expression systems such as Neuro 2A, COS 7, E. coli and yeast cells in order to assess the catalytic activities of the expressed protein in comparison with brain microsomes. We will examine psychoactive substrate binding of the expressed unique proteins versus wild type forms. These approaches at various levels will enable us to define CYP P450 forms expressed uniquely in brain and assess their functional roles in metabolizing psychoactive drugs.

描述(申请人提供)：利用原位杂交和免疫组织化学检测技术，在肝脏中表达的一些细胞色素P450也在人和大鼠的脑中表达。此外，使用人和大鼠脑微粒体，已经证明药物和类固醇的P450依赖的代谢表明大脑细胞色素P450是催化活性的。最近，在接受检查的20名身体捐赠者中，只有9人的大脑中发现了一种独特的CYP2D形式。这种在Neuro 2A细胞中克隆和表达的CYP2D形式具有独特的催化活性，可以将可待因专门转化为吗啡，从而不仅展示了独特的大脑特异性定位，而且还展示了一种特定的功能活性。这项提议将集中在这个和其他在人脑中独特表达的P450形式的表达的定义上。这一目标将通过定义这些形式在大脑中的区域分布作为性别、年龄和种族的函数，以及通过定义这些表达的纯化的P450对临床用于治疗大脑疾病的一组神经活性精神活性药物的催化能力来实现。该药物小组将包括抗抑郁药氟西汀和丙咪嗪，抗精神病药氯丙嗪和氟哌啶醇，抗焦虑药物阿普唑仑，抗多动药物哌醋甲酯，止痛药乙基吗啡和苯丙胺苯丙胺。我们将确定这些药物在人脑微粒体中的催化活性。我们将使用从大脑区域分离的RNA和原位杂交技术来确定这些新形式的区域表达。我们将克隆的独特形式在异源表达系统中进行表达，如Neuro 2A、COS 7、大肠杆菌和酵母细胞，以评估表达蛋白的催化活性，并与脑微粒体进行比较。我们将检查表达的独特蛋白与野生型形式的精神活性底物结合。这些不同水平的方法将使我们能够定义在大脑中唯一表达的CYP P450形式，并评估它们在精神活性药物代谢中的功能作用。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite.

DOI：
10.1371/journal.pone.0002337
发表时间：
2008-06-11
期刊：
PloS one
影响因子：
3.7
作者：
Agarwal V;Kommaddi RP;Valli K;Ryder D;Hyde TM;Kleinman JE;Strobel HW;Ravindranath V
通讯作者：
Ravindranath V

Unique cytochromes P450 in human brain: implication in disease pathogenesis.

人脑中独特的细胞色素 P450：对疾病发病机制的影响。