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CYP2E1-dependent toxicity and oxidative stress in HepG2 cells.
Free Radic Biol Med. 2001 Dec 15; 31(12):1539-43.FR

Abstract

Induction of CYP2E1 by ethanol is one of the central pathways by which ethanol generates a state of oxidative stress in hepatocytes. To study the biochemical and toxicological actions of CYP2E1, our laboratory established HepG2 cell lines which constitutively overexpress CYP2E1 and characterized these cells with respect to ethanol toxicity. Addition of ethanol or an unsaturated fatty acid such as arachidonic acid or iron was toxic to the CYP2E1-expressing cells but not control cells. This toxicity was associated with elevated lipid peroxidation and could be prevented by antioxidants and inhibitors of CYP2E1. Apoptosis occurred in the CYP2E1-expressing cells exposed to ethanol, arachidonic acid, or iron. Removal of GSH caused a loss of viability in the CYP2E1-expressing cells even in the absence of added toxin or pro-oxidant. This was associated with mitochondrial damage and decreased mitochondrial membrane potential. Surprisingly, CYP2E1-expressing cells had elevated GSH levels, due to transcriptional activation of gamma glutamyl cysteine synthetase. Similarly, levels of catalase, alpha-, and microsomal glutathione transferase were also increased, suggesting that upregulation of these antioxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. While it is likely that several mechanisms contribute to alcohol-induced liver injury, the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis may contribute to the toxic action of ethanol on the liver. HepG2 cell lines overexpressing CYP2E1 may be a valuable model to characterize the biochemical and toxicological properties of CYP2E1.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029, USA. arthur.cederbaum@mssm.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.
Review

Language

eng

PubMed ID

11744327

Citation

Cederbaum, A I., et al. "CYP2E1-dependent Toxicity and Oxidative Stress in HepG2 Cells." Free Radical Biology & Medicine, vol. 31, no. 12, 2001, pp. 1539-43.
Cederbaum AI, Wu D, Mari M, et al. CYP2E1-dependent toxicity and oxidative stress in HepG2 cells. Free Radic Biol Med. 2001;31(12):1539-43.
Cederbaum, A. I., Wu, D., Mari, M., & Bai, J. (2001). CYP2E1-dependent toxicity and oxidative stress in HepG2 cells. Free Radical Biology & Medicine, 31(12), 1539-43.
Cederbaum AI, et al. CYP2E1-dependent Toxicity and Oxidative Stress in HepG2 Cells. Free Radic Biol Med. 2001 Dec 15;31(12):1539-43. PubMed PMID: 11744327.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CYP2E1-dependent toxicity and oxidative stress in HepG2 cells. AU - Cederbaum,A I, AU - Wu,D, AU - Mari,M, AU - Bai,J, PY - 2001/12/18/pubmed PY - 2002/3/23/medline PY - 2001/12/18/entrez SP - 1539 EP - 43 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 31 IS - 12 N2 - Induction of CYP2E1 by ethanol is one of the central pathways by which ethanol generates a state of oxidative stress in hepatocytes. To study the biochemical and toxicological actions of CYP2E1, our laboratory established HepG2 cell lines which constitutively overexpress CYP2E1 and characterized these cells with respect to ethanol toxicity. Addition of ethanol or an unsaturated fatty acid such as arachidonic acid or iron was toxic to the CYP2E1-expressing cells but not control cells. This toxicity was associated with elevated lipid peroxidation and could be prevented by antioxidants and inhibitors of CYP2E1. Apoptosis occurred in the CYP2E1-expressing cells exposed to ethanol, arachidonic acid, or iron. Removal of GSH caused a loss of viability in the CYP2E1-expressing cells even in the absence of added toxin or pro-oxidant. This was associated with mitochondrial damage and decreased mitochondrial membrane potential. Surprisingly, CYP2E1-expressing cells had elevated GSH levels, due to transcriptional activation of gamma glutamyl cysteine synthetase. Similarly, levels of catalase, alpha-, and microsomal glutathione transferase were also increased, suggesting that upregulation of these antioxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. While it is likely that several mechanisms contribute to alcohol-induced liver injury, the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, and GSH homeostasis may contribute to the toxic action of ethanol on the liver. HepG2 cell lines overexpressing CYP2E1 may be a valuable model to characterize the biochemical and toxicological properties of CYP2E1. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/11744327/CYP2E1_dependent_toxicity_and_oxidative_stress_in_HepG2_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891584901007432 DB - PRIME DP - Unbound Medicine ER -