Early Alcoholic Liver Injury: Formation of Protein Adducts with Acetaldehyde and Lipid Peroxidation Products, and Expression of CYP 2E1 AND CYP 3A
Abstract
The formation of protein adducts with reactive aldehydes resulting from ethanol metabolism and lipid peroxidation has been suggested to play a role in the pathogenesis of alcoholic liver injury. To gain further insight on the contribution of such aldehydes in alcoholic liver disease, we have compared the appearance of acetaldehyde, malondialdehyde, and 4‐hydroxynonenal adducts with the expression of cytochrome P‐450IIE1, and cytochrome P‐4503A enzymes in the liver of rats fed alcohol with a high‐fat diet for 2 to 4 weeks according to the Tsukamoto‐French procedure and in control rats (high‐fat liquid diet or no treatment). Urine alcohol and serum aminotransferase levels were recorded, and the liver pathology was scored from 0 to 10 according to the presence of steatosis, inflammation, necrosis, and fibrosis. The ethanol treatment resulted in the accumulation of fat, mild necrosis and inflammation, and a mean liver pathology score of 3 (range: 1 to 5). Liver specimens from the ethanol‐fed animals with early alcohol‐induced liver injury were found to contain perivenular, hepatocellular acetaldehyde adducts. Malondialdehyde and 4‐hydroxynonenal adducts were also present showing a more diffuse staining pattern with occasional sinusoidal reactions. In the control animals, a faint positive reaction for the hydroxynonenal adduct occurred in some of the animals fed the high fat diet, whereas no specific staining was observed in the livers from the animals receiving no treatment Expression of both CYP2E1 and CYP3A correlated with the amount of protein adducts in the liver of alcohol‐treated rats. Distinct CVP2E1 ‐positive immunohistochemistry was seen in 3 of 7 of the ethanol‐fed animals. In 5 of 7 of the ethanol‐fed animals, the staining intensities for CYP3A markedly exceeded those obtained from the controls. The present findings indicate that acetaldehyde and lipid peroxidatjon‐derived adducts are generated in the early phase of alcohol‐induced liver disease. The formation of protein adducts appears to be accompanied by induction of both CVP2E1 and CVP3A.
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After ethanol intake, AA, MDA, and 4-HNE adducts are produced rapidly in the hepatic centrilobular zone, sinusoids, and HSCs as well as on the hepatocyte surface; their amounts are markedly elevated in the early phase of ALD, suggesting a role in initial development and progression of ALD.
“After ethanol intake, AA, MDA, and 4-HNE adducts are produced rapidly in the hepatic centrilobular zone (zone III), sinusoids, and HSCs as well as on the hepatocyte surface in the liver.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [216]
CYP2E1 contributes to the production of AA and MAA adducts, as demonstrated in experimental rodent and cell culture models.
“In particular, CYP2E1 contributes to the production of AA and MAA adducts, as demonstrated in experimental rodent and cell culture models137,180,216,273.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [216]
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- Authors
- Niemelä, O., Parkkila, S., Pasanen, M., Limuro, Y., Bradford, B., & Thurman, R. G.
- Affiliations
- University of Oulu (FI)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Niemelä, Onni
- Venue
- Alcoholism: Clinical and Experimental Research
- Publisher
- Wiley
- Published
- 1998-12
- Volume
- 22
- Issue
- 9
- Pages
- 2118-2124
- ISSN
- 0145-6008 (ISSN-L)
- 1530-0277
- OpenAlex
- W2165883049
- Cited by
- 107
- References
- 47
- Citations by year
- 2025: 4 · 2024: 4 · 2022: 1 · 2021: 6 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 4
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Alcoholism Clinical and Experimental Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- alcoholic liver injury, acetaldehyde, protein adducts, lipid peroxidation, malondialdehyde, 4-hydroxynonenal, CYP2E1, CYP3A, alcohol metabolism, high-fat diet, liver pathology, enzyme induction, liver necrosis, steatosis
- MeSH terms
- Acetaldehyde, Ethanol, Animals, Aryl Hydrocarbon Hydroxylases, Cytochrome P-450 Enzyme System, Liver, Liver Diseases, Alcoholic, Male, Malondialdehyde, Oxidoreductases, N-Demethylating, Lipid Peroxidation, Gene Expression Regulation, Enzymologic, Rats, Wistar, Cytochrome P-450 CYP2E1, Rats, Cytochrome P-450 CYP3A
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