Acetaldehyde Effect on Protein-Adduct Formation and GI Tract Substrate Transport

乙醛对蛋白质加合物形成和胃肠道底物运输的影响

基本信息

批准号：
7275147
负责人：
SCOTT J FISHER
金额：
$ 2.53万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-10 至 2009-04-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7275147
关键词：
Acetaldehyde Acetates Acetylation Acute Acyclovir Adhesions Affect Albumins Alcohol consumption Alcohols Aldehydes Amino Acids Angiotensin-Converting Enzyme Inhibitors Area Arrhythmia Binding Binding Proteins Binding Sites Biological Availability Blood Coagulation Factor Blood Pressure Breast C57BL/6 Mouse CCL21 gene Caco-2 Cells Captopril Cardiovascular Diseases Carrier Proteins Cefazolin Cell Line Cell model Cell physiology Cells Chemicals Chronic Cirrhosis Classification Colorectal Condition Coronary heart disease Cyclosporine Daily Data Analyses Dependence Dipeptides Disease Disruption Dose Doxorubicin Drug Compounding Drug Interactions Drug Kinetics Drug Transport Electrical Resistance Enalapril Enzyme Induction Enzyme Interaction Enzymes Epithelial Erythrocyte Membrane Esophageal Esters Ethanol Ethanol Metabolism Evaluation Event Exhibits Fatty Acids Gastrointestinal tract structure Gene Expression Gene Expression Regulation Genes Harvest Hemoglobin Hepatic Hepatitis Hepatotoxicity Histone Deacetylation Human Genome In Vitro Intestines Inulin Investigation Knock-out Laboratories Literature Liver Liver diseases Lysine Malignant Neoplasms Mannitol Membrane Proteins Membrane Transport Proteins Metabolism Microarray Analysis Microsomes Modification Monobactams Mus Nature Oral Paclitaxel Pancreas Penicillins Peptide Receptor Permeability Personal Satisfaction Pharmaceutical Preparations Phenotype Plasma Plasma Proteins Population Post-Translational Protein Processing Process Proteins Purpose RNA Regulation Reporting Research Risk Schiff Bases Signal Transduction Stroke Sucrose Therapeutic Thrombin Tight Junctions Tissues Transcriptional Regulation Tubulin Ubenimex Ubiquitination Wild Type Mouse Work Xenobiotics absorption adduct alcohol effect alcohol research cell growth regulation clinically relevant cytotoxic day desire drinking ethyl glucuronide gastrointestinal in vivo intestinal epithelium macromolecule mouse model novel strategies occludin protein function transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): The effects of ethanol and its primary aldehyde metabolite, acetaldehyde, on the absorption of substrates in the gastrointestinal tract have received little scientific inquiry. Acetaldehyde has been shown to increase paracellular permeability, form stable protein-adducts, which are associated with liver toxicity, and to interfere with cellular regulation, however, its effects on the modulation of epithelial transporters have not been examined. Thus, the purpose of this work is to examine the effects of acetylation on clinically relevant, broad substrate specific transporters, each with different mechanisms of transport. The hypothesis is that the metabolism of ethanol, leads to acetylation of transporter proteins and tight junction proteins, which modulate oral absorption of a variety of clinically relevant drugs. Further, the metabolism of exogenous ethanol causes random chemical acetylation of amino acid residues that can affect cellular regulation and therefore, affect transporter protein function. A systematic evaluation of the effects of acetaldehyde on the permeability of structurally diverse substrates is desirable. The specific aims of this project are to examine the influence of acetaldehyde on gene regulation in the gastrointestinal tract. To examine the effect of acetaldehyde on the actions of transporter proteins and consequences to cellular uptake in vitro. To evaluate the modulation of paracellular permeability of therapeutic macromolecules that traditionally display low oral bioavailability. And to evaluate the in vivo effects of alcohol drinking on drug uptake. This is a novel approach to alcohol research, since the majority of alcohol research involves observing xenobiotic interactions with alcohol, the induction of ethanol metabolizing enzymes in the liver, and its possible toxic consequences. The pharmacokinetic interactions of drugs and alcohol may not be solely due to enzyme interactions, but also to the interaction of acetaldehyde, drugs and transporter proteins in the body. This work will examine the effects of ethanol metabolites on drug absorption in the gastrointestinal tract prior to hepatic enzyme induction. Identification of acetaldehyde adducts and effect on protein function allows for the opportunity to examine the consquences to drug uptake in populations that are unable to refrain from drinking while concurrently receiving treatment for other disease states, such as cancer or liver disease.

描述（由申请人提供）：乙醇及其初级醛代谢物乙醛对胃肠道中底物吸收的影响很少受到科学调查。乙醛已被证明可以增加细胞旁通透性，形成与肝毒性相关的稳定的蛋白质加合物，并干扰细胞调节，然而，其对上皮转运蛋白调节的影响尚未得到研究。因此，这项工作的目的是检查乙酰化对临床相关的广泛底物特异性转运蛋白的影响，每种转运蛋白具有不同的转运机制。假设乙醇的代谢导致转运蛋白和紧密连接蛋白的乙酰化，从而调节多种临床相关药物的口服吸收。此外，外源乙醇的代谢会导致氨基酸残基发生随机化学乙酰化，从而影响细胞调节，从而影响转运蛋白功能。需要系统地评估乙醛对结构不同的基质的渗透性的影响。该项目的具体目的是研究乙醛对胃肠道基因调控的影响。研究乙醛对转运蛋白作用的影响以及对体外细胞摄取的影响。评估传统上口服生物利用度较低的治疗性大分子的细胞旁通透性调节。并评估饮酒对药物摄取的体内影响。这是酒精研究的一种新颖方法，因为大多数酒精研究涉及观察异生素与酒精的相互作用、肝脏中乙醇代谢酶的诱导及其可能的毒性后果。药物和酒精的药代动力学相互作用可能不仅仅归因于酶的相互作用，还归因于体内乙醛、药物和转运蛋白的相互作用。这项工作将在肝酶诱导之前检查乙醇代谢物对胃肠道药物吸收的影响。乙醛加合物的鉴定及其对蛋白质功能的影响使我们有机会检查那些无法克制饮酒同时接受其他疾病状态（例如癌症或肝病）治疗的人群的药物摄取后果。