Increased expression of cytochrome P450 2E1 induces heme oxygenase-1 through ERK MAPK pathway.
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.
Gong
Pengfei
P
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029, USA.
Cederbaum
Arthur I
AI
Nieto
Natalia
N
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D017930:Genes, Reporter; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress; D011720:Pyrazoles / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D000975:Antioxidants; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000431:Ethanol; D003577:Cytochrome P-450 Enzyme System; D002374:Catalase; D019392:Cytochrome P-450 CYP2E1; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C510163:CYP3A4 protein, human; D020928:Mitogen-Activated Protein Kinases