Cytochrome P450 2E1 (CYP2E1)-Dependent Production of a 37-kDa Acetaldehyde–Protein Adduct in the Rat Liver
Abstract
Ethanol-inducible cytochrome P450 2E1 (CYP2E1) has been shown to be involved in the metabolism of both ethanol and acetaldehyde. Acetaldehyde, produced from ethanol metabolism, is highly reactive and can form various protein adducts. In this study, we investigated the role of CYP2E1 in the production of a 37-kDa acetaldehyde-protein adduct. Rats were pairfed an isocaloric control or an alcohol liquid diet with and without cotreatment of YH439, an inhibitor of CYP2E1 gene transcription, for 4 weeks. The soluble proteins from rat livers of each group were separated on SDS-polyacrylamide gels followed by immunoblot analysis using specific antibodies against the 37-kDa protein acetaldehyde adduct. In addition, catalytic activities of the enzymes involved in alcohol and acetaldehyde metabolism were measured and compared with the adduct level. Immunoblot analysis revealed that the 37-kDa adduct, absent in the pair-fed control, was evident in alcohol-fed rats but markedly reduced by YH439 treatment. Immunohistochemical analysis also showed that the 37-kDa adduct is predominantly localized in the pericentral region of the liver where CYP2E1 protein is mainly expressed. This staining disappeared in the pericentral region after YH439 treatment. The levels of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase isozymes were unchanged after YH439 treatment. However, the level of the 37-kDa protein adduct positively correlated with the hepatic content of P4502E1. These data indicate that the 37-kDa adduct could be produced by CYP2E1-mediated ethanol metabolism in addition to the ADH-dependent formation.
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After chronic and/or large amounts of ethanol intake, CYP2E1 is involved in ethanol metabolism through an NADPH-dependent pathway; CYP2E1 expression and activity are usually induced by ethanol and other substances such as dietary fats, and this induction contributes to alcohol- and nonalcohol-induced pathophysiology.
“After chronic and/or large amounts of ethanol intake, CYP2E1, the major component of the microsomal ethanol oxidizing system (MEOS) with a higher km (~10 mM for ethanol) than that of ADH (km <1 mM for ethanol), is also involved in ethanol metabolism through an NADPH-dependent pathway.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [137]
Some AA adducts are produced in a CYP2E1-dependent manner.
“In addition, some of these AA adducts are produced in a CYP2E1-dependent manner137,181.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [137]
CYP2E1 was shown to be involved in the production of hepatic AA- and AA-MDA adducts.
“Since CYP2E1 was shown to be involved in the production of hepatic AA- and AA-MDA adducts137,181,250, it would be of interest to study the direct role of CYP2E1 in alcohol-mediated AGE production and GI pathologies.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [137]
Naturally occurring CYP2E1 inhibitors and synthetic compounds can prevent alcohol-induced oxidative stress and the formation of various adducts, including AA adducts and AA-MAA adducts.
“can prevent alcohol-induced oxidative stress and the formation of various adducts, including AA adducts137 and AA-MAA adducts53,285”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [137]
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 [137]
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- Authors
- Jeong, K.-S., Soh, Y., Jeng, J., Felder, M. R., Hardwick, J. P., & Song, B. J.
- Affiliations
- National Institutes of Health (US)
- University of South Carolina (US)
- Northeast Ohio Medical University (US)
- Corresponding author
- Song, Byoung J.
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 2000-12
- Volume
- 384
- Issue
- 1
- Pages
- 81-87
- ISSN
- 0003-9861 (ISSN-L)
- OpenAlex
- W1973947246
- Cited by
- 33
- References
- 39
- Citations by year
- 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2019: 1 · 2016: 1 · 2015: 1 · 2014: 3 · 2013: 3
- FWCI
- 1.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Biochemistry and Biophysics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- CYP2E1, acetaldehyde, alcohol metabolism, liver, alcohol dehydrogenase, aldehyde dehydrogenase, alcohol-induced liver injury
- MeSH terms
- Acetaldehyde, Alcohol Dehydrogenase, Ethanol, Aldehyde Dehydrogenase, Animals, Body Weight, Immunohistochemistry, Liver, Male, Molecular Weight, Thiazoles, Immunoblotting, Anticarcinogenic Agents, Rats, Wistar, Cytochrome P-450 CYP2E1, Rats
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