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

描述(由申请人提供)：乙醇及其主要的乙醛代谢物乙醛对胃肠道底物吸收的影响几乎没有得到科学研究。乙醛可以增加细胞旁通透性，形成稳定的蛋白质加合物，与肝脏毒性有关，并干扰细胞调节，但其对上皮转运蛋白的调节作用尚未被研究。因此，这项工作的目的是研究乙酰化对临床相关的广泛底物特异性转运蛋白的影响，每种转运蛋白都有不同的转运机制。假设乙醇的代谢导致转运蛋白和紧密连接蛋白的乙酰化，这调节了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的随机化学乙酰化，这可能会影响细胞调节，从而影响转运蛋白的功能。系统地评估乙醛对不同结构底物的渗透性的影响是可取的。这个项目的具体目的是检测乙醛对胃肠道基因调控的影响。目的：研究乙醛对转运蛋白的作用及其对细胞摄取的影响。评估传统上表现为低口服生物利用度的治疗性大分子对细胞旁通透性的调节。并评价饮酒对体内药物摄取的影响。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物与酒精的相互作用，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，还可能是乙醛、药物和体内转运蛋白的相互作用。这项工作将研究乙醇代谢产物在肝酶诱导之前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人们有机会研究在接受癌症或肝病等其他疾病治疗的同时无法不饮酒的人群中药物摄取的后果。

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.