The long-term goal of this project is to understand the role of CYP2E1, ALDH2, and ALDH1 genes which encode alcohol-metabolizing enzymes, in alcohol-induced oxidative stress and toxicity. Chronic alcohol abuse results in a variety of pathological effects, including liver fibrosis and cirrhosis. Some of the toxic effects of ethanol have now been linked to ethanol metabolism. Ethanol consumption causes a CYP2E1 induction, which is associated with increased levels of acetaldehyde, generation of reactive oxygen species (ROS), lipid peroxidation, mitochondrial GSH depletion, and increased collagen synthesis. Most of the toxic effects of ethanol are due to acetaldehyde and potential molecular targets include proteins, lipids and mitochondrial DNA. Genetic polymorphisms exist in human CYP2E1 and ALDH2 genes that may influence the risk for developing alcoholic liver disease. Interestingly, chronic ethanol consumption mimics the oxidative stress seen in aging animals, particularly in liver. Although the importance of oxidative stress in cellular damage is well appreciated, the molecular mechanisms by which alcohol induces oxidative stress and causes liver damage are still unknown. Our hypothesis predicts that chronic alcohol consumption induces oxidative stress and cellular injury that is associated with imbalances in the production/detoxification of intermediates (acetaldehyde) or reactants (ROS and lipid peroxidative products) of ethanol metabolism. To test this hypothesis, the role of Cyp2e1, Aldh2 and Aldh1 genes in ethanol metabolism and liver in injury will be investigated by using transgenic mouse lines having homozygous disruptions in these genes. For the 5-year period of this grant application, we therefore propose to:
Specific Aim 1 : Develop conventional, as well as inducible, Aldh2 and Aldh1 knockout transgenic mouse lines;
Specific Aim 2 : Use the Aldh2, Aldh1 and a Cyp2e1 knockout mouse lines to study the role of these genes in ethanol/acetaldehyde pharmacokinetics and metabolism;
Specific Aim 3 : Use the Cyp2e1 Aldh2 and Aldh1 knockout mouse lines to test the hypothesis that CYP2E1 (involved in ROS production), ALDH2 and ALDH1 I (involved in acetaldehyde detoxification) are involved in the alcohol-induced oxidative stress that leads to liver injury. Liver injury will be studied in parallel with: i) oxidative stress, ii) assessment of lipid peroxidation, iii) characterization of molecular targets of oxidative stress-mediated injury including mitochondrial DNA damage and genes involved in collagen synthesis and degradation. These studies will greatly enhance our understanding of genetic factors involved in alcohol toxicity.
| Deitrich, Richard A; Petersen, Dennis; Vasiliou, Vasilis (2007) Removal of acetaldehyde from the body. Novartis Found Symp 285:23-40;discussion 40-51, 198-9 |
| Vasiliou, Vasilis; Ziegler, Thomas L; Bludeau, Pequita et al. (2006) CYP2E1 and catalase influence ethanol sensitivity in the central nervous system. Pharmacogenet Genomics 16:51-8 |
| Bhave, Sanjiv V; Hoffman, Paula L; Lassen, Natalie et al. (2006) Gene array profiles of alcohol and aldehyde metabolizing enzymes in brains of C57BL/6 and DBA/2 mice. Alcohol Clin Exp Res 30:1659-69 |
| Zimatkin, Sergey M; Pronko, Sergey P; Vasiliou, Vasilis et al. (2006) Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 30:1500-5 |
| Panayiotidis, Mihalis I; Stabler, Sally P; Ahmad, Aftab et al. (2006) Activation of a novel isoform of methionine adenosyl transferase 2A and increased S-adenosylmethionine turnover in lung epithelial cells exposed to hyperoxia. Free Radic Biol Med 40:348-58 |
| Lassen, Natalie; Estey, Tia; Tanguay, Robert L et al. (2005) Molecular cloning, baculovirus expression, and tissue distribution of the zebrafish aldehyde dehydrogenase 2. Drug Metab Dispos 33:649-56 |
| Vasiliou, Vasilis; Pappa, Aglaia; Estey, Tia (2004) Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism. Drug Metab Rev 36:279-99 |
| Sophos, Nickolas A; Vasiliou, Vasilis (2003) Aldehyde dehydrogenase gene superfamily: the 2002 update. Chem Biol Interact 143-144:5-22 |
| Manzer, Rizwan; Qamar, Lubna; Estey, Tia et al. (2003) Molecular cloning and baculovirus expression of the rabbit corneal aldehyde dehydrogenase (ALDH1A1) cDNA. DNA Cell Biol 22:329-38 |
| Vasiliou, Vasilis; Qamar, Lubna; Pappa, Aglaia et al. (2003) Involvement of the electrophile responsive element and p53 in the activation of hepatic stellate cells as a response to electrophile menadione. Arch Biochem Biophys 413:164-71 |
Showing the most recent 10 out of 15 publications
