Regulation of genes involved in hepatic drug elimination by female hormones

女性激素对肝脏药物消除相关基因的调控

基本信息

批准号：
7660455
负责人：
Hyunyoung Jeong
金额：
$ 23.05万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-20 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7660455
关键词：
Adverse effects Affect Aftercare Behavior Binding Biological Assay Blood Blood flow CYP1A2 gene CYP2C19 gene CYP2C9 gene CYP2D6 gene CYP3A4 gene Caffeine Cells Clinical Clinical Research Cytochrome P450 Data Deoxyribonuclease I Dextromethorphan Diclofenac Disease Dose Drug Kinetics Electrophoretic Mobility Shift Assay Enhancers Enzymes Estradiol Estrogen Receptors Estrogens Excretory function Female Fetus Gene Expression Regulation Genes Glucuronosyltransferase Goals Gonadal Hormones Hand Hepatic Hepatocyte Hormonal Hormonal Change Hormone Responsive Hormones Human Human Genome In Vitro Individual Kidney Knowledge Liver Mediating Medical Medicine Mephenytoin Metabolic Metabolic Pathway Midazolam Modeling Mothers Mutation Oral Oral Contraceptives Outcome Pharmaceutical Preparations Pharmacotherapy Physiological Plasma Proteins Population Pregnancy Pregnanes Pregnant Women Production Progesterone Protein Binding RNA Reporting Role Sampling System Testing Time Treatment Protocols Western Blotting Woman Women&apos s Group Xenobiotics absorption base design drug metabolism follow-up hormone regulation lamotrigine men public health relevance receptor research study

项目摘要

DESCRIPTION (provided by applicant): During pregnancy, it is ideal for pregnant women to avoid use of medications to protect the developing fetus from any potential adverse effects. But pre-existing medical conditions or disorders to which pregnant women are susceptible mandate continued use of medicines. This unavoidable drug treatment requires accurate pharmacokinetic information because under- or over-exposure may result in detrimental clinical outcomes not only in the mother but also in the fetus. Clinical studies in pregnant women have suggested that pharmacokinetic profiles of many drugs are altered during pregnancy. Generally, oral absorption of drugs is delayed, and distribution and renal excretion of drugs increase. Hepatic drug metabolism, on the other hand, has been suggested to change in a metabolic pathway-dependent manner in pregnancy. However, it is currently unclear whether the data reflect true changes in expression or function of hepatic drug metabolizing enzymes, apart from changes in other factors, such as changes in protein binding of a drug or blood flow to the liver. This necessitates an in vitro system where changes in hepatic drug metabolism can be exclusively examined. Physiological changes accompanying pregnancy are expected to be responsible for altered drug metabolism in pregnancy. The most pronounced change in pregnant women is a dramatic increase in the production of female hormones such as estrogen and progesterone. The elevated hormones may be responsible for altered hepatic drug metabolism in pregnancy. At the high concentrations attained in pregnancy, female hormones have functions different from their conventional role as gonadal hormones. Progesterone binds to and activates a transcriptional regulator pregnane xenobiotic receptor (PXR), which induces expression of major drug metabolizing enzymes including cytochrome P450 enzymes and UDP- glucuronosyltransferases (UGTs). Furthermore, estrogen promotes the expression of UGT1A4 and -1A9 in HepG2 cells, mediated via the action of estrogen receptor-? (ER?). Based on the evidence, we propose to test the hypothesis that the hormones elevated during pregnancy, estrogen and progesterone, globally modulate expression of hepatic drug metabolizing enzymes, leading to altered hepatic elimination of drugs. The following specific aims are designed accordingly. (1) Determine the enzyme-specific effects of estrogen and progesterone on hepatic drug metabolism. The functional significance of hormonal regulation will be investigated by examining how the hepatic elimination rates of various probe drugs change in human hepatocytes after treatment of the hepatocytes with female hormones. (2) Define the mechanisms by which estradiol regulates the expression of UGT1A4 and -1A9. Electrophoretic mobility shift assay, DNase I protection, and mutation assays will be performed. (3) Identify estradiol- or progesterone-responsive genes in the liver. Microarray experiments (Affymetrix Human Genome U133 plus 2.0 GeneChip array) will be performed using RNA samples prepared from human hepatocytes after hormone treatment. PUBLIC HEALTH RELEVANCE: Medication use by pregnant women is common, but drug behaviors in this population are generally different from those in non-pregnant women or men. Understanding of these changes is important in determination of optimal dosing regimen. We propose to investigate mechanisms of such changes in drug behaviors. The knowledge obtained from this study can be expanded to optimize drug therapy in other groups of women, such as oral contraceptive users, thus benefiting women in general.

描述（由申请人提供）：在怀孕期间，孕妇最好避免使用药物，以保护发育中的胎儿免受任何潜在的不利影响。但孕妇易患的现有疾病或疾病要求继续使用药物。这种不可避免的药物治疗需要准确的药代动力学信息，因为暴露不足或过度暴露可能不仅对母亲而且对胎儿产生有害的临床结果。孕妇的临床研究表明，许多药物的药代动力学特征在怀孕期间发生了改变。一般药物口服吸收延迟，药物分布和肾排泄增加。另一方面，肝脏药物代谢被认为在妊娠期间以代谢途径依赖性方式发生变化。然而，目前尚不清楚这些数据是否反映了肝脏药物代谢酶表达或功能的真实变化，除了其他因素的变化，例如药物的蛋白质结合或流向肝脏的血流的变化。这就需要一个可以专门检查肝脏药物代谢变化的体外系统。妊娠期间的生理变化预计会导致妊娠期药物代谢的改变。孕妇最显着的变化是雌激素和黄体酮等雌性激素的产生急剧增加。升高的激素可能是导致妊娠期肝脏药物代谢改变的原因。在怀孕期间达到高浓度时，雌性激素具有不同于其作为性腺激素的常规作用的功能。黄体酮结合并激活转录调节剂孕烷异生素受体 (PXR)，该受体诱导主要药物代谢酶的表达，包括细胞色素 P450 酶和 UDP-葡萄糖醛酸基转移酶 (UGT)。此外，雌激素通过雌激素受体-β的作用介导HepG2细胞中UGT1A4和-1A9的表达。（呃？）。基于这些证据，我们建议检验以下假设：怀孕期间雌激素和黄体酮等激素升高，全局调节肝脏药物代谢酶的表达，导致肝脏药物消除发生改变。据此设计了以下具体目标。 (1)测定雌激素和孕激素对肝脏药物代谢的酶特异性作用。将通过检查用女性激素处理肝细胞后各种探针药物的肝脏消除率如何变化来研究激素调节的功能意义。 (2)明确雌二醇调节UGT1A4和-1A9表达的机制。将进行电泳迁移率变动测定、DNase I 保护和突变测定。 (3) 鉴定肝脏中雌二醇或孕酮反应基因。将使用激素处理后的人肝细胞制备的 RNA 样本进行微阵列实验（Affymetrix 人类基因组 U133 加 2.0 GeneChip 阵列）。公共卫生相关性：孕妇用药很常见，但该人群的用药行为通常与非孕妇或男性不同。了解这些变化对于确定最佳给药方案非常重要。我们建议研究药物行为这种变化的机制。从这项研究中获得的知识可以扩展到优化其他女性群体（例如口服避孕药使用者）的药物治疗，从而使广大女性受益。