Chronic alcohol abuse has a variety of pathological consequences including damage to liver, brain and other organs. Some of these pathological effects can be attributed to ethanol metabolism. Ethanol is metabolized to acetaldehyde by the alcohol dehydrogenase enzymes (ADHs), ethanol-inducible cytochrome P450 (CYP2E1) and catalase. Many of the toxic effects of ethanol are due to acetaldehyde and its actions on molecular targets viz. proteins, lipids and mitochondrial DNA. As a result, the role of acetaldehyde metabolism may be crucial for understanding the pathogenesis of tissue injury caused by alcohol consumption. Impaired acetaldehyde metabolism is associated with polymorphisms in the human aldehyde dehydrogenase (ALDH) enzymes;these may influence drinking behavior and risk for developing alcoholic liver disease. Mitochondrial ALDH2 and, to a lesser extent, cytosolic ALDH1A1 enzymes are known to play a major role in acetaldehyde detoxification. Human ALDH2 is polymorphic with 2 distinct alleles, ALDH2*1 and ALDH2*2. ALDH2*2 homozygous individuals are completely devoid of ALDH2 activity, whereas ALDH2*1/2*2 heterozygous individuals exhibit only 30-50% of the normal ALDH activity. This altered enzyme activity has physiological ramifications. For example, after equivalent amounts of alcohol are consumed, blood acetaldehyde levels in ALDH2*2 homozygous individuals are 6-20 times higher than those in ALDH2*1/2*1 individuals in whom acetaldehyde is hardly detectable. ALDH1B1 is a mitochondrial enzyme that is 75% identical to ALDH2 and also may be involved in acetaldehyde metabolism. Although there is a considerable amount of information about ALDH2 and ALDH1A1, very little is known about ALDH1B1. Our working hypothesis for this R21 grant application is two-fold. First, we hypothesize that the mitochondrial ALDH1B1 is a functional enzyme that protects cells by metabolizing acetaldehyde and lipid peroxidation-associated aldehydes. Second, we hypothesize that ALDH2*2 protein may inactivate other ALDHs by interacting with them. For the 2-year period of this application, we propose to characterize the human and mouse ALDH1B1 proteins in relation to: (a) enzymatic function (metabolism of acetaldehyde and lipid peroxidation aldehydes), (b) expression pattern in both mouse and human tissues, and (c) its protective role against aldehyde-induced toxicity and apoptosis. These will be studied using recombinant ALDH1B1 proteins and cell lines expressing, over-expressing or lacking this protein. In addition, we will determine whether ALDH2*2 protein inactivates both ALDH2*1 enzymes and ALDH1B1. This will be accomplished by studying the formation of heterotetramers using recombinant proteins and cell lines expressing these proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA017754-01
Application #
7523198
Study Section
Special Emphasis Panel (ZAA1-JJ (17))
Program Officer
Gentry, Thomas
Project Start
2009-06-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
1
Fiscal Year
2009
Total Cost
$219,604
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Matsumoto, Akiko; Arcaroli, John; Chen, Ying et al. (2017) Aldehyde dehydrogenase 1B1: a novel immunohistological marker for colorectal cancer. Br J Cancer 117:1537-1543
Monte, Andrew A; Heard, Kennon J; Campbell, Jenny et al. (2014) The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness. Acad Emerg Med 21:879-85
Brocker, Chad; Vasiliou, Melpomene; Carpenter, Sarah et al. (2013) Aldehyde dehydrogenase (ALDH) superfamily in plants: gene nomenclature and comparative genomics. Planta 237:189-210
Ioannou, Marilia; Serafimidis, Ioannis; Arnes, Luis et al. (2013) ALDH1B1 is a potential stem/progenitor marker for multiple pancreas progenitor pools. Dev Biol 374:153-63
Brocker, Chad; Thompson, David C; Vasiliou, Vasilis (2012) The role of hyperosmotic stress in inflammation and disease. Biomol Concepts 3:345-364
Koppaka, Vindhya; Thompson, David C; Chen, Ying et al. (2012) Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev 64:520-39
Chen, Ying; Orlicky, David J; Matsumoto, Akiko et al. (2011) Aldehyde dehydrogenase 1B1 (ALDH1B1) is a potential biomarker for human colon cancer. Biochem Biophys Res Commun 405:173-9
Brocker, Chad; Cantore, Miriam; Failli, Paola et al. (2011) Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive aldehyde and oxidative stress induced cytotoxicity. Chem Biol Interact 191:269-77
Jackson, Brian; Brocker, Chad; Thompson, David C et al. (2011) Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics 5:283-303
Chen, Ying; Johansson, Elisabet; Yang, Yi et al. (2010) Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis. J Hepatol 53:1085-94

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