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Murine Drinking Models in the Development of Pharmacotherapies for Alcoholism: Drinking in the Dark and Two-bottle Choice
Published on: January 7, 2019
Transgenic mouse models for alcohol metabolism, toxicity, and cancer
Claire Heit1, Hongbin Dong, Ying Chen
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA.
Abstract:
Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remain to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in alcohol consumption and dependence. Oxidative stress resulting from ethanol oxidation is one established pathogenic event in alcohol-induced toxicity. Ethanol metabolism generates free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and has been associated with diminished glutathione (GSH) levels as well as changes in other antioxidant mechanisms. In addition, the formation of protein and DNA adducts associated with the accumulation of ethanol-derived aldehydes can adversely affect critical biological functions and thereby promote cellular and tissue pathology. Animal models have proven to be valuable tools for investigating mechanisms underlying pathogenesis caused by alcohol. In this review, we provide a brief discussion on several animal models with genetic defects in alcohol-metabolizing enzymes and GSH-synthesizing enzymes and their relevance to alcohol research.
Insights
Alcohol abuse causes tissue damage and cancer through complex molecular mechanisms. Animal models with genetic defects in alcohol metabolism and antioxidant pathways help researchers understand these alcohol-related pathologies.
Area of Science:
- Biochemistry
- Toxicology
- Genetics
Background:
- Alcohol abuse is linked to significant tissue damage, including cancers, but the precise molecular mechanisms are not fully understood.
- Key enzymes in ethanol metabolism (ADH, CYP2E1, CAT, ALDH) and their genetic variations influence alcohol-related risks and dependence.
- Ethanol oxidation generates oxidative stress (ROS, RNS), depletes glutathione (GSH), and forms toxic adducts, contributing to cellular pathology.
Purpose of the Study:
- To review the molecular mechanisms of alcohol-induced tissue damage.
- To discuss the utility of animal models with genetic defects in alcohol metabolism and GSH synthesis for studying alcohol pathogenesis.
Main Methods:
- Review of existing literature on alcohol metabolism, oxidative stress, and adduct formation.
- Discussion of specific animal models with genetic alterations in enzymes critical for alcohol metabolism and antioxidant defense.
Main Results:
- Genetic polymorphisms in alcohol-metabolizing enzymes are associated with varied risks of alcohol-related tissue damage.
- Oxidative stress, ROS/RNS generation, GSH depletion, and aldehyde adducts are established pathogenic pathways in alcohol toxicity.
- Animal models provide valuable insights into the pathogenesis of alcohol-induced diseases.
Conclusions:
- Understanding the molecular basis of alcohol-induced tissue damage is crucial for developing effective interventions.
- Genetically modified animal models are essential tools for elucidating the complex mechanisms of alcohol-related diseases.
- Further research using these models can advance our knowledge of alcohol's impact on health.
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