Engineered Animal Models Designed for Investigating Ethanol Metabolism, Toxicity and Cancer

Abstract

Excessive consumption of alcohol is a leading cause of lifestyle-induced morbidity and mortality worldwide. Although long-term alcohol abuse has been shown to be detrimental to the liver, brain and many other organs, our understanding of the exact molecular mechanisms by which this occurs is still limited. In tissues, ethanol is metabolized to acetaldehyde (mainly by alcohol dehydrogenase and cytochrome p450 2E1) and subsequently to acetic acid by aldehyde dehydrogenases. Intracellular generation of free radicals and depletion of the antioxidant glutathione (GSH) are believed to be key steps involved in the cellular pathogenic events caused by ethanol. With continued excessive alcohol consumption, further tissue damage can result from the production of cellular protein and DNA adducts caused by accumulating ethanol-derived aldehydes. Much of our understanding about the pathophysiological consequences of ethanol metabolism comes from genetically-engineered mouse models of ethanol-induced tissue injury. In this review, we provide an update on the current understanding of important mouse models in which ethanol-metabolizing and GSH-synthesizing enzymes have been manipulated to investigate alcohol-induced disease.

Mechanisms of Ethanol-Induced Cerebellar Ataxia: Underpinnings of Neuronal Death in the Cerebellum

“…Some of these symptoms can be attributed to differentiation deficits in the cerebellar cortex and subsequent impairment in cerebellar coordinative controls on cognitive functions through the cerebello-cerebral loops. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase and cytochrome p450 2E1 and subsequently to acetic acid by aldehyde dehydrogenases [10]. Intracellular generation of free radicals and depletion of the antioxidant glutathione are vital steps in the cellular pathogenic events caused by ethanol [10].…”

“…Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase and cytochrome p450 2E1 and subsequently to acetic acid by aldehyde dehydrogenases [10]. Intracellular generation of free radicals and depletion of the antioxidant glutathione are vital steps in the cellular pathogenic events caused by ethanol [10]. In addition to such a classic view, recent studies using various animal models have shown diverse pathophysiological mechanisms.…”

“…For example, Zebrafish models clarified that ethanol exposure impaired mitochondrial bioenergetics, leading to a production of reactive oxygen species [11]. Furthermore, since ethanol metabolism is multifaceted, mouse models with genetic deficiencies in ethanol-metabolizing enzymes led to a deeper understanding of the multi-layered molecular pathways [10]. Similarly, studies using various methodologies have facilitated the elucidation of the mechanisms by which ethanol exposure impairs the adult and fetal cerebellum.…”

Zonisamide Ameliorated the Apoptosis and Inflammation in Cerebellar Tissue of Induced Alcohol Addiction Animal Model

“…Upon ingestion, alcohol is metabolized to acetaldehyde by alcohol dehydrogenase and cytochrome enzymes and eventually to acetic acid [37]. Throughout these steps, free radicals are generated, and cells are predisposed to oxidative stress, leading to cellular pathology [38]. Various studies have shown that alcohol exposure impairs mitochondrial function and elevates free radical production [39].…”