ESTROGEN & TRICYCLIC ANTIDEPRESSANT METABOLISM IN BRAIN

雌激素

• 批准号: 2246287
• 负责人: HENRY W STROBEL
• 金额: $ 17.66万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-01 至 1996-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2246287
• 关键词: RNA biosynthesis; amitriptyline; animal tissue; brain mapping; brain metabolism; complementary DNA; cytochrome P450; drug metabolism; enzyme reconstitution; enzyme substrate; estrogen receptors; estrogens; female; flavones; gene expression; hormone regulation /control mechanism; imipramine; isozymes; laboratory rat; northern blottings; nucleic acid hybridization; nucleic acid probes; oligonucleotides; ovariectomy; phenobarbital; phosphorus; protein purification; radionuclides; tricyclic antidepressant

The cytochrome P450 dependent mixed function oxidase system is found in many tissues of vertebrates and is responsible for the metabolism of a variety of therapeutically important drugs among them the tricyclic antidepressants. Recently our laboratory has shown the presence of cytochromes P450 forms b (P450IIB1) and c (P450IA1) using 32P DNA probes in a poly (A)+RNA hybridization assay. The hybridizable bands of both forms are inducible by phenobarbital of beta-napthoflavone, respectively, Furthermore, estrogen and the tricyclic antidepressants amitriptyline and imipramine increase the hybridization of form b. These preliminary data give rise to the hypothesis that brain cytochrome might play a role in antidepressant metabolism in brain and that estrogen levels may influence the expression of cytochromes P450 and in turn antidepressant metabolism. This proposal will test this hypothesis that brain cytochrome might play a role in antidepressant metabolism in brain and that estrogen levels may influence the expression of cytochromes P450 and in turn antidepressant metabolism. This proposal will test this hypothesis by identifying the cytochromes P450 present in brain and localizing them to specific brain areas using 32P labelled DNA or oligonucleotide probes to the various P450 isozymes. We will also characterize the effect of inducers (phenobarbital and beta-napthoflavone), antidepressant substrates (amitriptyline and imipramine), and estrogen on the expression of P450. We will also identify which P450s catalyze antidepressant metabolism in brain using purification and in vitro reconstitution of activity in assay techniques. We will assess the role of estrogen in the expression of brain cytochrome P450 by treating normal and ovarectomized rats with estrogen and other inducers and comparing P450 expression levels. These data will also be used in a correlation of estrogen responsive brain areas with those having estrogen receptors in order to assess how estrogen might exert is regulatory role on brain P450 expression. These studies may aid our understanding of the decreased efficacy of tricyclic antidepressant drugs in the treatment of post menopausal depression and provide a basis for addressing this depression.

细胞色素P450依赖的混合功能氧化酶系统被发现于 脊椎动物的许多组织，并负责代谢的一个 各种治疗上重要的药物，其中三环 抗抑郁药 最近，我们的实验室发现了 细胞色素P450的B型（P450 IIB 1）和C型（P450 IA 1 在poly（A）+RNA杂交测定中。 两者的杂交带 形式分别由苯巴比妥或β-萘酮诱导， 此外，雌激素和三环类抗抑郁药阿米替林和 丙咪嗪增加了B型的杂交。这些初步数据 提出了一个假设，即脑细胞色素可能在 抗抑郁药在大脑中的代谢和雌激素水平可能会影响 细胞色素P450的表达和抗抑郁药的代谢。 这项提议将验证这一假设，即大脑细胞色素可能发挥作用， 在大脑抗抑郁代谢中的作用，雌激素水平可能 影响细胞色素P450的表达，从而产生抗抑郁作用 新陈代谢. 本提案将通过确定 细胞色素P450存在于脑内，并定位于特定的脑内 使用32 P标记的DNA或寡核苷酸探针对不同的区域进行标记， P450同工酶。我们还将描述诱导剂的作用 （苯巴比妥和β-萘酮），抗抑郁底物 （阿米替林和丙咪嗪）和雌激素对P450表达的影响。 我们还将确定哪些P450催化抗抑郁药代谢， 在测定中使用脑的纯化和体外重建活性 技术. 我们将评估雌激素在表达中的作用， 脑细胞色素P450的治疗正常和卵巢切除大鼠 雌激素和其他诱导剂，并比较P450表达水平。这些 数据也将用于雌激素反应脑的相关性， 与那些有雌激素受体的区域，以评估如何 雌激素可能对脑组织P450表达具有调节作用。 这些 研究可能有助于我们理解三环类药物的疗效降低， 治疗绝经后抑郁症的抗抑郁药物， 为解决这一抑郁症提供了基础。