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

• 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
• 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

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（由申请方提供）：乙醇及其主要醛代谢产物乙醛对胃肠道中底物吸收的影响几乎没有科学研究。乙醛已被证明可增加细胞旁渗透性，形成稳定的蛋白加合物，这与肝毒性有关，并干扰细胞调节，然而，尚未检查其对上皮转运蛋白调节的影响。因此，这项工作的目的是研究乙酰化对临床相关的，广泛的底物特异性转运蛋白的影响，每个转运蛋白具有不同的转运机制。假设是乙醇的代谢导致转运蛋白和紧密连接蛋白的乙酰化，其调节各种临床相关药物的口服吸收。此外，外源性乙醇的代谢导致氨基酸残基的随机化学乙酰化，其可影响细胞调节，并因此影响转运蛋白功能。一个系统的评价乙醛对结构多样的基板的渗透性的影响是可取的。该项目的具体目标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及其对体外细胞摄取的影响。评价传统口服生物利用度低的治疗性大分子的细胞旁渗透性调节。并评价饮酒对药物摄取的体内影响。这是酒精研究的一种新方法，因为大多数酒精研究涉及观察异生物质与酒精的相互作用，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是由于酶的相互作用，而且还与乙醛、药物和转运蛋白在体内的相互作用有关。这项工作将检查乙醇代谢产物对肝酶诱导前胃肠道药物吸收的影响。乙醛加合物的鉴定和对蛋白质功能的影响允许有机会检查无法避免饮酒同时接受其他疾病状态（如癌症或肝病）治疗的人群中药物摄取的后果。