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Transcription factor Nrf2 protects HepG2 cells against CYP2E1 plus arachidonic acid-dependent toxicity.
J Biol Chem. 2006 May 26; 281(21):14573-9.JB

Abstract

Nrf2 is a transcription factor that regulates important antioxidant and phase II detoxification genes. Arachidonic acid (AA) causes CYP2E1-dependent toxicity in HepG2 cells. The ability of Nrf2 to protect against CYP2E1-dependent AA toxicity and its possible mechanism were evaluated. AA activates Nrf2 in CYP2E1-expressing HepG2 cells (E47 cells), increasing Nrf2 protein and mRNA levels, Nrf2 nuclear translocation, and Nrf2-ARE binding activity. These increases in Nrf2 are associated with elevated expression of Nrf2-regulated antioxidant genes. Overexpression of Nrf2 by transient transfection of plasmid Nrf2 confers resistance of E47 cells against AA toxicity. Blocking Nrf2 with small interfering RNA (siRNA)-Nrf2 potentiates the CYP2E1-dependent AA toxicity. This enhanced toxicity is accompanied by decreases of cellular GSH levels and increases in production of reactive oxygen species and lipid peroxidation. There is also a potentiation of mitochondrial damage in the presence of siRNA-Nrf2. The protective effects of Nrf2 against CYP2E1-dependent toxicity can be blocked by l-buthionine-(S,R)-sulfoximine, a specific inhibitor of glutamate-cysteine ligase, which is a rate-limiting enzyme in the synthesis of GSH and is regulated by Nrf2. Elevation of GSH by supplementing with glutathione ethyl ester can partially reverse the enhanced AA toxicity by siRNA-Nrf2. Moreover, in contrast to AA, l-buthionine-(S,R)-sulfoximine toxicity is not prevented by plasmid Nrf2 probably because protective GSH cannot be synthesized. Together, these results suggest that Nrf2, through up-regulation of glutamate-cysteine ligase and increase of GSH levels, protects against CYP2E1-dependent AA toxicity.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16551616

Citation

Gong, Pengfei, and Arthur I. Cederbaum. "Transcription Factor Nrf2 Protects HepG2 Cells Against CYP2E1 Plus Arachidonic Acid-dependent Toxicity." The Journal of Biological Chemistry, vol. 281, no. 21, 2006, pp. 14573-9.
Gong P, Cederbaum AI. Transcription factor Nrf2 protects HepG2 cells against CYP2E1 plus arachidonic acid-dependent toxicity. J Biol Chem. 2006;281(21):14573-9.
Gong, P., & Cederbaum, A. I. (2006). Transcription factor Nrf2 protects HepG2 cells against CYP2E1 plus arachidonic acid-dependent toxicity. The Journal of Biological Chemistry, 281(21), 14573-9.
Gong P, Cederbaum AI. Transcription Factor Nrf2 Protects HepG2 Cells Against CYP2E1 Plus Arachidonic Acid-dependent Toxicity. J Biol Chem. 2006 May 26;281(21):14573-9. PubMed PMID: 16551616.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Transcription factor Nrf2 protects HepG2 cells against CYP2E1 plus arachidonic acid-dependent toxicity. AU - Gong,Pengfei, AU - Cederbaum,Arthur I, Y1 - 2006/03/21/ PY - 2006/3/23/pubmed PY - 2006/7/11/medline PY - 2006/3/23/entrez SP - 14573 EP - 9 JF - The Journal of biological chemistry JO - J Biol Chem VL - 281 IS - 21 N2 - Nrf2 is a transcription factor that regulates important antioxidant and phase II detoxification genes. Arachidonic acid (AA) causes CYP2E1-dependent toxicity in HepG2 cells. The ability of Nrf2 to protect against CYP2E1-dependent AA toxicity and its possible mechanism were evaluated. AA activates Nrf2 in CYP2E1-expressing HepG2 cells (E47 cells), increasing Nrf2 protein and mRNA levels, Nrf2 nuclear translocation, and Nrf2-ARE binding activity. These increases in Nrf2 are associated with elevated expression of Nrf2-regulated antioxidant genes. Overexpression of Nrf2 by transient transfection of plasmid Nrf2 confers resistance of E47 cells against AA toxicity. Blocking Nrf2 with small interfering RNA (siRNA)-Nrf2 potentiates the CYP2E1-dependent AA toxicity. This enhanced toxicity is accompanied by decreases of cellular GSH levels and increases in production of reactive oxygen species and lipid peroxidation. There is also a potentiation of mitochondrial damage in the presence of siRNA-Nrf2. The protective effects of Nrf2 against CYP2E1-dependent toxicity can be blocked by l-buthionine-(S,R)-sulfoximine, a specific inhibitor of glutamate-cysteine ligase, which is a rate-limiting enzyme in the synthesis of GSH and is regulated by Nrf2. Elevation of GSH by supplementing with glutathione ethyl ester can partially reverse the enhanced AA toxicity by siRNA-Nrf2. Moreover, in contrast to AA, l-buthionine-(S,R)-sulfoximine toxicity is not prevented by plasmid Nrf2 probably because protective GSH cannot be synthesized. Together, these results suggest that Nrf2, through up-regulation of glutamate-cysteine ligase and increase of GSH levels, protects against CYP2E1-dependent AA toxicity. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/16551616/Transcription_factor_Nrf2_protects_HepG2_cells_against_CYP2E1_plus_arachidonic_acid_dependent_toxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)72398-7 DB - PRIME DP - Unbound Medicine ER -