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. ? ? ?
