Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration
Open accessAbstract
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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Interactions between acetaldehyde or MDA and cellular proteins lead to formation of MAA adducts, which are highly stable and resistant to rapid degradation; increased MAA adducts from alcohol exposure stimulate protein dysfunction and immune-induced tissue injury through interactions with TLR-3, TLR-6, calpain, collagen alpha-1 (XII) chain, procollagen type XIV alpha-1, protocadherin beta, or补体成分.
“Interactions between acetaldehyde or MDA and cellular proteins lead to the formation of MAA adducts, which are highly stable and resistant to rapid degradation178,179.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [178]
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BackgroundMethodInfluentialSelf-citationSeitz, H. K., & Neuman, M. G. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10040858 · Cited by 45 · see citing works
“MDA increases acetaldehyde-adduct formation significantly, resulting in the formation of a highly reactive, hybrid MDA–acetaldehyde adduct [142].”
BackgroundThiele, 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 · see citing works
“1 M phosphate buffer (PB) with 2 milligrams of S100 at 37°C overnight (Tuma et al., 1996).”
BackgroundMethodInfluentialSelf-citationAlcoholic macrocytosis–is there a role for acetaldehyde and adducts?
Niemelä, O. J., & Parkkila, S. (2004) · Addiction Biology · doi:10.1080/13556210410001674031 · Cited by 45 · see citing works
“The former species can react with acetaldehyde to generate hybrid adducts, which have been designated as MAA adducts.(46)”
BackgroundImmunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease
Shen, H.-Y., Liangpunsakul, S., Iwakiri, Y., Szabo, G., & Wang, H. (2025) · Cellular & Molecular Immunology · doi:10.1038/s41423-025-01291-w · Cited by 47 · see citing works
“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 · see citing works
Self-citationExposure 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 · see citing works
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 · see citing works
“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-citationThiele, 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 · see citing works
“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-citationVidali, 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 · see citing works
How to fix DNA-protein crosslinks
Kühbacher, U., & Duxin, J. P. (2020) · DNA repair · doi:10.1016/j.dnarep.2020.102924 · Cited by 40 · see citing works
Sergent, O., Griffon, B., Cillard, P., & Cillard, J. (2001) · Pathologie Biologie · doi:10.1016/s0369-8114(01)00244-9 · Cited by 38 · see citing works
The ubiquitin‐proteasome system and its role in ethanol‐induced disorders
Donohue, T. M. (2002) · Addiction Biology · doi:10.1080/135562101200100562 · Cited by 39 · see citing works
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 39 · see citing works
Haller, E., Lindner, W. F., & Lämmerhofer, M. (2014) · Analytica Chimica Acta · doi:10.1016/j.aca.2014.12.024 · Cited by 36 · see citing works
“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].”
BackgroundEthanol 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 · see citing works
Self-citationHyvärinen, 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 · see citing works
“Therefore, we have not used the prefix “MAA” in this article.”
MethodInfluentialVehkala, 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 · see citing works
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 · see citing works
Wyatt, T. A., Kharbanda, K. K., Tuma, D. J., et al. (2001) · Alcohol · doi:10.1016/s0741-8329(01)00177-x · Cited by 34 · see citing works
“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-citationThiele, 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 · see citing works
Self-citationFreeman, 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 · see citing works
Self-citationWorrall, 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 · see citing works
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 · see citing works
- Authors
- Tuma, D. J., Thiele, G. M., Xu, D., Klassen, L. W., & Sorrell, M. F.
- Affiliations
- United States Department of Veterans Affairs (US)
- ORCID
- Venue
- Hepatology
- Published
- 1996-04
- Volume
- 23
- Issue
- 4
- Pages
- 872-880
- ISSN
- 0270-9139 (ISSN-L)
- 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
- 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 › 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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