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Increased expression of cytochrome P450 2E1 induces heme oxygenase-1 through ERK MAPK pathway.
J Biol Chem. 2003 Aug 08; 278(32):29693-700.JB

Abstract

The inducible form of heme oxygenase (HO-1) is increased during oxidative injury, and this may be an important defense mechanism against such injury. Cytochrome P450 2E1 (CYP2E1) generates reactive oxygen species and promotes lipid peroxidation. In this study induction of HO-1 by CYP2E1 and the possible role of mitogen-activated protein kinase (MAPK) in this process were evaluated. HO-1 induction was observed in the livers of chronic alcohol-fed mice or pyrazole-treated rats, conditions known to elevate CYP2E1 levels. Increased levels of HO-1 were observed in HepG2 cells overexpressing CYP2E1 (E47 cells) compared with control HepG2 cells or HepG2 cells expressing CYP3A4. Expression of CYP2E1 in HepG2 cells transcriptionally activated the HO-1 gene, increasing HO-1 mRNA and protein expression and activity of a HO-1 reporter construct. CYP2E1 inhibitors and catalase blocked the increased production of reactive oxygen species as well as HO-1 induction. Increasing oxidative stress by the addition of arachidonic acid or depletion of glutathione further increased HO-1 induction. The phosphorylated form of ERK MAPK but not that of p38 or JNK MAPK was increased in E47 cells compared with the control C34 HepG2 cells. PD98059, a specific inhibitor of ERK MAPK, blocked the activity of a HO-1 reporter in E47 cells but not in C34 cells. These results suggest that increased CYP2E1 activity leads to induction of the HO-1 gene, and the ERK MAPK pathway is important in mediating this process. This induction may serve as an adaptive mechanism to protect the E47 cells against the CYP2E1-dependent oxidative stress.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

12777398

Citation

Gong, Pengfei, et al. "Increased Expression of Cytochrome P450 2E1 Induces Heme Oxygenase-1 Through ERK MAPK Pathway." The Journal of Biological Chemistry, vol. 278, no. 32, 2003, pp. 29693-700.
Gong P, Cederbaum AI, Nieto N. Increased expression of cytochrome P450 2E1 induces heme oxygenase-1 through ERK MAPK pathway. J Biol Chem. 2003;278(32):29693-700.
Gong, P., Cederbaum, A. I., & Nieto, N. (2003). Increased expression of cytochrome P450 2E1 induces heme oxygenase-1 through ERK MAPK pathway. The Journal of Biological Chemistry, 278(32), 29693-700.
Gong P, Cederbaum AI, Nieto N. Increased Expression of Cytochrome P450 2E1 Induces Heme Oxygenase-1 Through ERK MAPK Pathway. J Biol Chem. 2003 Aug 8;278(32):29693-700. PubMed PMID: 12777398.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased expression of cytochrome P450 2E1 induces heme oxygenase-1 through ERK MAPK pathway. AU - Gong,Pengfei, AU - Cederbaum,Arthur I, AU - Nieto,Natalia, Y1 - 2003/05/30/ PY - 2003/6/5/pubmed PY - 2003/9/25/medline PY - 2003/6/5/entrez SP - 29693 EP - 700 JF - The Journal of biological chemistry JO - J Biol Chem VL - 278 IS - 32 N2 - The inducible form of heme oxygenase (HO-1) is increased during oxidative injury, and this may be an important defense mechanism against such injury. Cytochrome P450 2E1 (CYP2E1) generates reactive oxygen species and promotes lipid peroxidation. In this study induction of HO-1 by CYP2E1 and the possible role of mitogen-activated protein kinase (MAPK) in this process were evaluated. HO-1 induction was observed in the livers of chronic alcohol-fed mice or pyrazole-treated rats, conditions known to elevate CYP2E1 levels. Increased levels of HO-1 were observed in HepG2 cells overexpressing CYP2E1 (E47 cells) compared with control HepG2 cells or HepG2 cells expressing CYP3A4. Expression of CYP2E1 in HepG2 cells transcriptionally activated the HO-1 gene, increasing HO-1 mRNA and protein expression and activity of a HO-1 reporter construct. CYP2E1 inhibitors and catalase blocked the increased production of reactive oxygen species as well as HO-1 induction. Increasing oxidative stress by the addition of arachidonic acid or depletion of glutathione further increased HO-1 induction. The phosphorylated form of ERK MAPK but not that of p38 or JNK MAPK was increased in E47 cells compared with the control C34 HepG2 cells. PD98059, a specific inhibitor of ERK MAPK, blocked the activity of a HO-1 reporter in E47 cells but not in C34 cells. These results suggest that increased CYP2E1 activity leads to induction of the HO-1 gene, and the ERK MAPK pathway is important in mediating this process. This induction may serve as an adaptive mechanism to protect the E47 cells against the CYP2E1-dependent oxidative stress. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/12777398/Increased_expression_of_cytochrome_P450_2E1_induces_heme_oxygenase_1_through_ERK_MAPK_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)84235-5 DB - PRIME DP - Unbound Medicine ER -