Cited by 246Alcohol Consumption and Health EffectsAntioxidant Activity and Oxidative StressProtein Interaction Studies and Fluorescence Analysis

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Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration

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Tuma, D J, Thiele, G M, Xu, D, Klassen, L W, Sorrell, M F·1996·Hepatology

DOI 10.1002/hep.510230431

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Abstract

Acetaldehyde and the lipid peroxidation-derived aldehyde malondialdehyde (MDA), are reactive compounds that are generated during ethanol metabolism in the liver, and both aldehydes have been shown to be capable of binding to proteins and forming stable adducts. Because similar concentrations of MDA and acetaldehyde can coexist in the liver during ethanol oxidation, protein adduct formation in the presence of both of these aldehydes was studied under both in vitro and in vivo conditions. When proteins were incubated in the presence of both MDA and acetaldehyde, MDA caused a marked and concentration-dependent increase in the stable binding of acetaldehyde to proteins. Maximum stimulation of binding occurred at approximately a fourfold molar excess of MDA relative to acetaldehyde when concentrations of 1.0 mmol/L and 0.1 mmol/L were tested. The formation of highly fluorescent product or products was associated with the MDA stimulation of acetaldehyde binding, indicating that new and distinct products were being generated. These hybrid adducts of MDA and acetaldehyde have been designated as MAA adducts. An affinity-purified polyclonal antibody was produced that specifically recognized MAA epitopes on proteins and did not cross-react with carrier proteins or proteins modified with either acetaldehyde or MDA alone. A quantitative competitive enzyme-linked immunosorbent assay (ELISA) was developed and detected the presence of MAA-modified proteins in liver cytosol from ethanol-fed rats but not in pair-fed controls. Quantification of the data from the competitive ELISA indicated the presence of approximately 75 pmoles protein-bound MAA per milligram liver cytosol proteins of the ethanol-fed animals. These results indicate that acetaldehyde and MDA can react together in a synergistic manner and generate hybrid adducts (MAA-adducts) and further suggest that MAA adducts may represent a major species of adducts formed in the liver during ethanol metabolism in vivo .

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Recent Advances in Alcohol‐Induced Adduct Formation
Freeman, T. L., Tuma, D. J., Thiele, G. M., Klassen, L. W., Worrall, S., Niemelä, O., Parkkila, S., Emery, P. W., & Preedy, V. R. (2005) · Alcoholism: Clinical and Experimental Research · doi:10.1097/01.alc.0000171484.52201.52 · Cited by 48
Self-citation
Malondialdehyde–acetaldehyde-adducted protein inhalation causes lung injury
Wyatt, T. A., Kharbanda, K. K., McCaskill, M. L., Tuma, D. J., Yanov, D. A., DeVasure, J. M., & Sisson, J. H. (2011) · Alcohol · doi:10.1016/j.alcohol.2011.09.001 · Cited by 47
“…free, low endotoxin, Sigma, St. Louis, MO), SP-D or SP-A with an equimolar (1 mmol/L) solution of MDA and acetaldehyde (Aldrich Chemical Co, Milwaukee, WI) for 3 days at 37°C in a sealed polypropylene vessel in a non-oxidizing atmosphere as detailed in our earlier publication (Tuma et al., 1996).”
Self-citation
The Chemistry and Biological Effects of Malondialdehyde‐Acetaldehyde Adducts
Thiele, G. M., Worrall, S., Tuma, D. J., Klassen, L. W., Wyatt, T. A., & Nagata, N. (2001) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2001.tb02399.x · Cited by 46
Self-citation
T cell proliferative responses to malondialdehyde–acetaldehyde haptenated protein are scavenger receptor mediated
Willis, M. S., Thiele, G. M., Tuma, D. J., & Klassen, L. W. (2003) · International Immunopharmacology · doi:10.1016/s1567-5769(03)00136-x · Cited by 44
Self-citation
Malondialdehyde–acetaldehyde–protein adducts increase secretion of chemokines by rat hepatic stellate cells
Kharbanda, K. K., Todero, S. L., Shubert, K. A., Sorrell, M. F., & Tuma, D. J. (2001) · Alcohol · doi:10.1016/s0741-8329(01)00174-4 · Cited by 45
“We have shown previously that the majority of MAA– protein adduct formation occurs in hepatocytes after ethanol consumption (Tuma et al., 1996).”
BackgroundMethodInfluentialSelf-citation
The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology
Seitz, H. K., & Neuman, M. G. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10040858 · Cited by 45
“MDA increases acetaldehyde-adduct formation significantly, resulting in the formation of a highly reactive, hybrid MDA–acetaldehyde adduct [142].”
Background
Autoimmune Hepatitis Induced by Syngeneic Liver Cytosolic Proteins Biotransformed by Alcohol Metabolites
Thiele, G. M., Duryee, M. J., Willis, M. S., Tuma, D. J., Radio, S. J., Hunter, C. D., Schaffert, C. S., & Klassen, L. W. (2010) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2010.01309.x · Cited by 45
“1 M phosphate buffer (PB) with 2 milligrams of S100 at 37°C overnight (Tuma et al., 1996).”
BackgroundMethodInfluentialSelf-citation
Alcoholic macrocytosis–is there a role for acetaldehyde and adducts?
Niemelä, O. J., & Parkkila, S. (2004) · Addiction Biology · doi:10.1080/13556210410001674031 · Cited by 45
“The former species can react with acetaldehyde to generate hybrid adducts, which have been designated as MAA adducts.(46)”
Background
Immunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease
Shen, H., Liangpunsakul, S., Iwakiri, Y., Szabó, G., & Wang, H. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01291-w · Cited by 49
“While enhanced alcohol metabolism may seem protective, elevated CYP2E1 accelerates ethanol oxidation, resulting in higher acetaldehyde production and excessive reactive oxygen species (ROS) generation, including hydroxyethyl radicals, superoxide anions, and hydroxyl radicals [27, 28].”
Aldehyde-modified proteins as mediators of early inflammation in atherosclerotic disease
Antoniak, D. T., Duryee, M. J., Mikuls, T. R., Thiele, G. M., & Anderson, D. R. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.09.003 · Cited by 45
Self-citation
Exposure to ethanol induces oxidative damage in the pituitary gland
Ren, J.-C., Banan, A., Keshavarzian, A., Zhu, Q., LaPaglia, N., McNulty, J. A., Emanuele, N., & Emanuele, M. A. (2005) · Alcohol · doi:10.1016/j.alcohol.2005.03.005 · Cited by 44
Rat sinusoidal liver endothelial cells (SECs) produce pro-fibrotic factors in response to adducts formed from the metabolites of ethanol
Thiele, G. M., Duryee, M. J., Freeman, T. L., Sorrell, M. F., Willis, M. S., Tuma, D. J., & Klassen, L. W. (2005) · Biochemical Pharmacology · doi:10.1016/j.bcp.2005.08.014 · Cited by 43
“Another metabolic product of ethanol consumption is acetaldehyde, which is also produced in the liver, and has been shown to interact with malondialdehyde to form the stable protein adduct called malondialdehyde– acetaldehyde-adduct (MAA) [11].”
BackgroundSelf-citation
Malondialdehyde-acetaldehyde (MAA) modified proteins induce pro-inflammatory and pro-fibrotic responses by liver endothelial cells
Thiele, G. M., Duryee, M. J., Willis, M. S., Sorrell, M. F., Freeman, T. L., Tuma, D. J., & Klassen, L. W. (2004) · Comparative Hepatology · doi:10.1186/1476-5926-2-s1-s25 · Cited by 43
“Two of these metabolites, malondialdehyde (MDA) and acetaldehyde (AA), have been shown to synergistically bind to proteins (adduct) to form a product termed MAA [9].”
Self-citation
Immune responses against oxidative stress-derived antigens are associated with increased circulating tumor necrosis factor-α in heavy drinkers
Vidali, M., Hietala, J., Occhino, G., Ivaldi, A., Sutti, S., Niemelä, O. J., & Albano, E. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.04.012 · Cited by 41
How to fix DNA-protein crosslinks
Kühbacher, U., & Duxin, J. P. (2020) · DNA repair · doi:10.1016/j.dnarep.2020.102924 · Cited by 43
Alcool et stress oxydatif
Sergent, O., Griffon, B., Cillard, P., & Cillard, J. (2001) · Pathologie Biologie · doi:10.1016/s0369-8114(01)00244-9 · Cited by 38
The ubiquitin‐proteasome system and its role in ethanol‐induced disorders
Donohue, T. M. (2002) · Addiction Biology · doi:10.1080/135562101200100562 · Cited by 39
Gut microbiome as a therapeutic target for liver diseases
Singh, T. P., Kadyan, S., Devi, H., Park, G., & Nagpal, R. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121685 · Cited by 40
Gold nanoparticle–antibody conjugates for specific extraction and subsequent analysis by liquid chromatography–tandem mass spectrometry of malondialdehyde-modified low density lipoprotein as biomarker for cardiovascular risk
Haller, E., Lindner, W. F., & Lämmerhofer, M. (2014) · Analytica Chimica Acta · doi:10.1016/j.aca.2014.12.024 · Cited by 38
“For example,MDA can react with the e-amino group of lysine residues of proteins such as apolipoprotein B-100 (apo B-100) and such a reaction product was found in atherosclerotic lesions [13–22].”
Background
Ethanol promotes intestinal tumorigenesis in the MIN mouse. Multiple intestinal neoplasia.
Roy, H. K., Gulizia, J. M., Karolski, W. J., et al. (2002) · PubMed · Cited by 36
Self-citation
Recognition of Malondialdehyde-modified Proteins by the C Terminus of Complement Factor H Is Mediated via the Polyanion Binding Site and Impaired by Mutations Found in Atypical Hemolytic Uremic Syndrome
Hyvärinen, S., Uchida, K., Varjosalo, M. T., Jokela, R., & Jokiranta, T. S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.527416 · Cited by 35
“Therefore, we have not used the prefix “MAA” in this article.”
MethodInfluential
Plasma IgA antibody levels to malondialdehyde acetaldehyde-adducts are associated with inflammatory mediators, obesity and type 2 diabetes
Vehkala, L., Ukkola, O. H., Kesäniemi, Y. A., Kähönen, M. A. P., Nieminen, M. S., Salomaa, V. V., Jula, A., & Hörkkö, S. (2013) · Annals of Medicine · doi:10.3109/07853890.2013.841322 · Cited by 36
Role of MGST1 in reactive intermediate-induced injury
Schaffert, C. S. (2011) · World Journal of Gastroenterology · doi:10.3748/wjg.v17.i20.2552 · Cited by 34
Malondialdehyde–acetaldehyde-adducted bovine serum albumin activates protein kinase C and stimulates interleukin-8 release in bovine bronchial epithelial cells
Wyatt, T. A., Kharbanda, K. K., Tuma, D. J., & Sisson, J. H. (2001) · Alcohol · doi:10.1016/s0741-8329(01)00177-x · Cited by 34
“The MAA-modified BSA used in this study has been characterized to be free of contaminating single aldehyde–adducted BSA (Kearley et al., 1999; Tuma et al., 1996).”
BackgroundMethodSelf-citation
Formation and Immunological Properties of Aldehyde-derived Protein Adducts following Alcohol Consumption
Thiele, G. M., Klassen, L. W., & Tuma, D. J. (2008) · Methods in Molecular Biology™ · doi:10.1007/978-1-59745-242-7_17 · Cited by 33
Self-citation
Aldehydes in Cigarette Smoke React with the Lipid Peroxidation Product Malonaldehyde to Form Fluorescent Protein Adducts on Lysines
Freeman, T. L., Haver, A. C., Duryee, M. J., Tuma, D. J., Klassen, L. W., Hamel, F. G., White, R. L., Rennard, S. I., & Thiele, G. M. (2005) · Chemical Research in Toxicology · doi:10.1021/tx0500676 · Cited by 32
Self-citation
Protein adducts in type I and type II fibre predominant muscles of the ethanol‐fed rat: preferential localisation in the sarcolemmal and subsarcolemmal region
Worrall, S., Niemelä, O. J., Parkkila, S., Peters, T. J., & Preedy, V. R. (2001) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2001.00848.x · Cited by 33
Characterization in mice of the immunological properties of five allergenic acid anhydrides
Dearman, R. J., Warbrick, E. V., Humphreys, I. R., & Kimber, I. (2000) · Journal of Applied Toxicology · doi:10.1002/(sici)1099-1263(200005/06)20:3 · Cited by 54

Authors: Tuma, D. J., Thiele, G. M., Xu, D., Klassen, L. W., & Sorrell, M. F.
Affiliations: United States Department of Veterans Affairs (US)
ORCID: Thiele, G M
Xu, D
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 1996-04
Volume: 23
Issue: 4
Pages: 872-880
ISSN: 0270-9139 (ISSN-L)
DOI: 10.1002/hep.510230431
OpenAlex: W2021937351
Cited by: 245
References: 0
Citations by year: 2026: 5 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 12 · 2021: 6 · 2020: 7 · 2019: 2 · 2018: 8 · 2017: 7 · 2016: 6 · 2015: 7 · 2014: 10 · 2013: 18 · 2012: 8
FWCI: 4.18
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 7092 d)
Locations: Hepatology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01aa004961-18)
National Institute on Alcohol Abuse and Alcoholism (AA-04961, AA07818)
Topics: Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
Keywords: acetaldehyde, malondialdehyde, protein adducts, alcohol metabolism, liver, lipid peroxidation, polyclonal antibodies, competitive ELISA, liver cytosol
MeSH terms: Acetaldehyde, Ethanol, Animals, Enzyme-Linked Immunosorbent Assay, Liver, Male, Malondialdehyde, Protein Binding, Rabbits, Serum Albumin, Bovine, Rats, Wistar, Rats

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Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration

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