Glutathione Depletion in CYP2E1-Expressing Liver Cells Induces Toxicity Due to the Activation of p38 Mitogen-Activated Protein Kinase and Reduction of Nuclear Factor-κB DNA Binding Activity
- 14 June 2004
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 66 (3), 749-760
- https://doi.org/10.1124/mol.104.002048
Abstract
Depletion of glutathione (GSH) from CYP2E1-expressing cells by treatment with l-buthionine sulfoximine (BSO) causes decreased cell viability. The possible role of mitogen-activated protein kinases (MAPK) in this toxicity was evaluated. SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole], an inhibitor of p38 MAPK decreased the BSO-dependent toxicity in HepG2 E47 cells, which express CYP2E1 and in hepatocytes from pyrazole-treated rats. Inhibitors of extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, and c-Jun amino-terminal kinase were not protective. SB203580 did not prevent the loss of GSH nor lower the increase in reactive oxygen production; hence, protection by SB203580 was downstream of the elevated oxidative stress. Treatment with BSO caused activation of p38 MAPK whereas activation of nuclear factor-κB (NF-κB) was decreased; these effects were prevented by SB203580. We speculated that the decrease in NF-κB activation prevented production of hepatoprotective factors. One such factor could be nitric oxide (NO); indeed a NO donor decreased the BSO plus CYP2E1-dependent toxicity, whereas inhibition of inducible NO synthase (iNOS) potentiated toxicity. BSO treatment down-regulated iNOS and lowered NO levels, reactions blocked by SB203580; however, protection by SB203580 was the same in the absence or presence of an iNOS inhibitor, indicating that recovery of iNOS and NO production was not the mechanism by which SB203580 afforded protection against the BSO plus CYP2E1-dependent toxicity. Presumably other protective factors besides nitric oxide may be produced from activated NF-κB when p38 MAPK is inhibited by SB203580. These results suggest that the activation of p38 MAPK by BSO treatment in CYP2E1-expressing liver cells cause a loss in NF-κB-dependent production of hepatoprotective factors. This loss, coupled to CYP2E1-generated oxidant stress, synergize to promote cell injury.This publication has 37 references indexed in Scilit:
- Redox Regulation of Reactive Oxygen Species-Induced p38 MAP Kinase Activation and Barrier Dysfunction in Lung Microvascular Endothelial CellsAntioxidants and Redox Signaling, 2003
- Mechanisms for sensitization to TNF-induced apoptosis by acute glutathione depletion in murine hepatocytesHepatology, 2003
- Role of p38 MAPK in CYP2E1-dependent Arachidonic Acid ToxicityOnline Journal of Public Health Informatics, 2003
- Glutathione disulfide induces apoptosis in U937 cells by a redox‐mediated p38 mitogen‐activated protein kinase pathwayThe FASEB Journal, 2002
- Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stressHepatology, 2001
- Regulation by intracellular glutathione of TNF-α-induced p38 MAP kinase activation and RANTES production by human pulmonary vascular endothelial cellsAllergy, 2000
- Opposing Effects of ERK and JNK-p38 MAP Kinases on ApoptosisScience, 1995
- Function and Activation of NF-kappaB in the Immune SystemAnnual Review of Immunology, 1994
- Impaired uptake of glutathione by hepatic mitochondria from chronic ethanol-fed rats. Tracer kinetic studies in vitro and in vivo and susceptibility to oxidant stress.JCI Insight, 1991
- Effect of chronic ethanol feeding on rat hepatocytic glutathione. Compartmentation, efflux, and response to incubation with ethanol.JCI Insight, 1987