Inhibition of CYP2E1 leads to decreased malondialdehyde–acetaldehyde adduct formation in VL-17A cells under chronic alcohol exposure
Abstract
Aim Ethanol metabolism leads to the formation of acetaldehyde and malondialdehyde. Acetaldehyde and malondialdehyde can together form malondialdehyde-acetaldehyde (MAA) adducts. The role of alcohol dehydrogenase (ADH) and cytochrome P4502E1 (CYP2E1) in the formation of MAA-adducts in liver cells has been investigated.Main methods Chronic ethanol treated VL-17A cells over-expressing ADH and CYP2E1 were pretreated with the specific CYP2E1 inhibitor - diallyl sulfide or ADH inhibitor - pyrazole or ADH and CYP2E1 inhibitor - 4-methyl pyrazole. Malondialdehyde, acetaldehyde or MAA-adduct formation was measured along with assays for viability, oxidative stress and apoptosis.Key findings Inhibition of CYP2E1 with 10 μM diallyl sulfide or ADH with 2mM pyrazole or ADH and CYP2E1 with 5mM 4-methyl pyrazole led to decreased oxidative stress and toxicity in chronic ethanol (100 mM) treated VL-17A cells. In vitro incubation of VL-17A cell lysates with acetaldehyde and malondialdehyde generated through ethanol led to increased acetaldehyde (AA)-, malondialdehyde (MDA)-, and MAA-adduct formation. Specific inhibition of CYP2E1 or ADH and the combined inhibition of ADH and CYP2E1 greatly decreased the formation of the protein aldehyde adducts. Specific inhibition of CYP2E1 led to the greatest decrease in oxidative stress, toxicity and protein aldehyde adduct formation, implicating that CYP2E1 accelerates the formation of protein aldehyde adducts which can be an important mechanism for alcohol mediated liver injury.Significance CYP2E1-mediated metabolism of ethanol leads to increased AA-, MDA-, and MAA-adduct formation in liver cells which may aggravate liver injury.
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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 [181]
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 [181]
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- Authors
- Swaminathan, K., Clemens, D. L., & Dey, A.
- Affiliations
- Anna University, Chennai (IN)
- University of Nebraska Medical Center (US)
- Corresponding author
- Dey, Aparajita
- ORCID
- Clemens, Dahn L.
- Venue
- Life Sciences
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 92
- Issue
- 6-7
- Pages
- 325-336
- ISSN
- 0024-3205 (ISSN-L)
- OpenAlex
- W2024806044
- Cited by
- 23
- References
- 38
- Citations by year
- 2025: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 6 · 2014: 1 · 2013: 1
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Life Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Nebraska Medical Center
- Council of Scientific and Industrial Research, India
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- CYP2E1, alcohol dehydrogenase, chronic ethanol exposure, diallyl sulfide, pyrazole derivatives, 4-methylpyrazole, oxidative stress, apoptosis, liver injury, protein aldehyde adducts, alcohol metabolism
- MeSH terms
- Fomepizole, Acetaldehyde, Alcohol Dehydrogenase, Ethanol, Allyl Compounds, Cell Line, Cell Survival, Drug Administration Schedule, Enzyme Inhibitors, Humans, Malondialdehyde, Pyrazoles, Sulfides, Apoptosis, Reactive Oxygen Species, Cytochrome P-450 CYP2E1, Caspase 3, Hep G2 Cells, Cytochrome P-450 CYP2E1 Inhibitors
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