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The effect of CYP2E1-dependent oxidant stress on activity of proteasomes in HepG2 cells.
J Pharmacol Exp Ther. 2005 Oct; 315(1):304-12.JP

Abstract

A reduction in proteasome activity and accumulation of oxidized proteins may play a role in alcoholic liver disease. The current study assessed proteasome peptidase activities and oxidative modifications of proteasomes during oxidative stress generated by CYP2E1. The model of toxicity by arachidonic acid (AA) and iron [ferric-nitrilotriacetate (Fe-NTA)] in HepG2 cells overexpressing CYP2E1 (E47 cells) and control C34 cells was used. AA/Fe-NTA treatment decreased trypsin-like (T-L) activity of the proteasome in E47 cells but not in C34 cells. This inhibition was abolished by antioxidants. Chymotrypsin-like activity of the proteasome was increased in E47 cells, and activity was not altered by AA/Fe-NTA treatment. There were no changes in content of subunits of 20S proteasomes or 19S regulator ATPase subunits S4 and p42 by AA/Fe-NTA treatment. An increased content of the PA28alpha subunit of the 11S regulator of proteasomes was detected in E47 cells. In proteasome pellets, the decline of T-L activity was accompanied by increased content of carbonyl adducts, suggesting oxidative modification of proteasomes. Higher levels of ubiquitinated, 3-nitrotyrosine- and 4-hydroxynonenal-modified proteins and lower levels of free ubiquitin were detected in untreated E47 cells in comparison with C34 cells. Accumulation of protein cross-linked, detergent-insoluble aggregates was increased with AA/Fe-NTA treatment in E47 cells. Thus, reactive oxygen species generated upon CYP2E1-dependent oxidative stress mediated a decline in T-L proteasome function, increased carbonyl adducts in proteasomes, and promoted protein aggregate formation; this may alter the balance among protein oxidation, ubiquitination, and degradation.

Authors+Show Affiliations

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16002458

Citation

Kessova, Irina G., and Arthur I. Cederbaum. "The Effect of CYP2E1-dependent Oxidant Stress On Activity of Proteasomes in HepG2 Cells." The Journal of Pharmacology and Experimental Therapeutics, vol. 315, no. 1, 2005, pp. 304-12.
Kessova IG, Cederbaum AI. The effect of CYP2E1-dependent oxidant stress on activity of proteasomes in HepG2 cells. J Pharmacol Exp Ther. 2005;315(1):304-12.
Kessova, I. G., & Cederbaum, A. I. (2005). The effect of CYP2E1-dependent oxidant stress on activity of proteasomes in HepG2 cells. The Journal of Pharmacology and Experimental Therapeutics, 315(1), 304-12.
Kessova IG, Cederbaum AI. The Effect of CYP2E1-dependent Oxidant Stress On Activity of Proteasomes in HepG2 Cells. J Pharmacol Exp Ther. 2005;315(1):304-12. PubMed PMID: 16002458.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of CYP2E1-dependent oxidant stress on activity of proteasomes in HepG2 cells. AU - Kessova,Irina G, AU - Cederbaum,Arthur I, Y1 - 2005/07/07/ PY - 2005/7/9/pubmed PY - 2005/12/13/medline PY - 2005/7/9/entrez SP - 304 EP - 12 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 315 IS - 1 N2 - A reduction in proteasome activity and accumulation of oxidized proteins may play a role in alcoholic liver disease. The current study assessed proteasome peptidase activities and oxidative modifications of proteasomes during oxidative stress generated by CYP2E1. The model of toxicity by arachidonic acid (AA) and iron [ferric-nitrilotriacetate (Fe-NTA)] in HepG2 cells overexpressing CYP2E1 (E47 cells) and control C34 cells was used. AA/Fe-NTA treatment decreased trypsin-like (T-L) activity of the proteasome in E47 cells but not in C34 cells. This inhibition was abolished by antioxidants. Chymotrypsin-like activity of the proteasome was increased in E47 cells, and activity was not altered by AA/Fe-NTA treatment. There were no changes in content of subunits of 20S proteasomes or 19S regulator ATPase subunits S4 and p42 by AA/Fe-NTA treatment. An increased content of the PA28alpha subunit of the 11S regulator of proteasomes was detected in E47 cells. In proteasome pellets, the decline of T-L activity was accompanied by increased content of carbonyl adducts, suggesting oxidative modification of proteasomes. Higher levels of ubiquitinated, 3-nitrotyrosine- and 4-hydroxynonenal-modified proteins and lower levels of free ubiquitin were detected in untreated E47 cells in comparison with C34 cells. Accumulation of protein cross-linked, detergent-insoluble aggregates was increased with AA/Fe-NTA treatment in E47 cells. Thus, reactive oxygen species generated upon CYP2E1-dependent oxidative stress mediated a decline in T-L proteasome function, increased carbonyl adducts in proteasomes, and promoted protein aggregate formation; this may alter the balance among protein oxidation, ubiquitination, and degradation. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16002458/The_effect_of_CYP2E1_dependent_oxidant_stress_on_activity_of_proteasomes_in_HepG2_cells_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16002458 DB - PRIME DP - Unbound Medicine ER -