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Role of phosphatidylinositol 3-kinase/AKT as a survival pathway against CYP2E1-dependent toxicity.
J Pharmacol Exp Ther. 2006 Jul; 318(1):360-72.JP

Abstract

The objective of this work was to evaluate the possible role of PI3-kinase/AKT as a survival pathway against CYP2E1-dependent toxicity. E47 cells (HepG2 cells transfected with human CYP2E1 cDNA) exposed to 25 microM iron-nitrilotriacetate+5 microM arachidonic acid (AA+Fe) developed higher toxicity than C34 cells (HepG2 cells transfected with empty plasmid). Toxicity was associated with increased oxidative stress and activation of calcium-dependent hydrolases calpain and phospholipase A2. Treatment of E47, but not C34 cells, with arachidonic acid and iron (AA+Fe) led to a decrease in the phosphorylation state of AKT. 2-(4-Morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), a specific inhibitor of PI3-kinase, produced a further decrease of phosphorylated AKT in AA+Fe-treated E47 cells. LY294002 and down-regulation of endogenous AKT with small interference RNAs increased the toxicity of AA+Fe in E47 cells. Toxicity of AA+Fe in rat hepatocytes was also increased by LY294002. LY294002 did not affect phospholipase A2 or calpain activation, CYP2E1 activity, or lipid peroxidation elicited by AA+Fe. alpha-Tocopherol prevented both AA+Fe and AA+Fe+LY294002-induced toxicity and decrease of phosphorylated AKT. LY294002 potentiated AA+Fe-induced loss of mitochondrial membrane potential and ATP, whereas overexpression of constitutively active AKT partially prevented mitochondrial impairment and toxicity. Mitochondrial permeability transition inhibitors prevented both AA+Fe and AA+Fe+LY294002-induced toxicity and decrease of mitochondrial membrane potential. These results suggest that: i) AA+Fe+CYP2E1-induced oxidative stress decreases AKT activation; ii) AKT inactivation induces mitochondrial impairment associated with opening of the permeability transition pore but is not dependent on the activation state of bad, glycogen synthase kinase-3beta, mammalian target of rapamycin, or bcl-xL; and iii) PI3-kinase/AKT may serve as a survival pathway against CYP2E1-dependent toxicity.

Authors+Show Affiliations

Department of Pharmacology and Biological Chemistry, Box 1603, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. andres.caro@mssm.eduNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16624972

Citation

Caro, Andres A., and Arthur I. Cederbaum. "Role of Phosphatidylinositol 3-kinase/AKT as a Survival Pathway Against CYP2E1-dependent Toxicity." The Journal of Pharmacology and Experimental Therapeutics, vol. 318, no. 1, 2006, pp. 360-72.
Caro AA, Cederbaum AI. Role of phosphatidylinositol 3-kinase/AKT as a survival pathway against CYP2E1-dependent toxicity. J Pharmacol Exp Ther. 2006;318(1):360-72.
Caro, A. A., & Cederbaum, A. I. (2006). Role of phosphatidylinositol 3-kinase/AKT as a survival pathway against CYP2E1-dependent toxicity. The Journal of Pharmacology and Experimental Therapeutics, 318(1), 360-72.
Caro AA, Cederbaum AI. Role of Phosphatidylinositol 3-kinase/AKT as a Survival Pathway Against CYP2E1-dependent Toxicity. J Pharmacol Exp Ther. 2006;318(1):360-72. PubMed PMID: 16624972.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of phosphatidylinositol 3-kinase/AKT as a survival pathway against CYP2E1-dependent toxicity. AU - Caro,Andres A, AU - Cederbaum,Arthur I, Y1 - 2006/04/19/ PY - 2006/4/21/pubmed PY - 2006/8/15/medline PY - 2006/4/21/entrez SP - 360 EP - 72 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 318 IS - 1 N2 - The objective of this work was to evaluate the possible role of PI3-kinase/AKT as a survival pathway against CYP2E1-dependent toxicity. E47 cells (HepG2 cells transfected with human CYP2E1 cDNA) exposed to 25 microM iron-nitrilotriacetate+5 microM arachidonic acid (AA+Fe) developed higher toxicity than C34 cells (HepG2 cells transfected with empty plasmid). Toxicity was associated with increased oxidative stress and activation of calcium-dependent hydrolases calpain and phospholipase A2. Treatment of E47, but not C34 cells, with arachidonic acid and iron (AA+Fe) led to a decrease in the phosphorylation state of AKT. 2-(4-Morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), a specific inhibitor of PI3-kinase, produced a further decrease of phosphorylated AKT in AA+Fe-treated E47 cells. LY294002 and down-regulation of endogenous AKT with small interference RNAs increased the toxicity of AA+Fe in E47 cells. Toxicity of AA+Fe in rat hepatocytes was also increased by LY294002. LY294002 did not affect phospholipase A2 or calpain activation, CYP2E1 activity, or lipid peroxidation elicited by AA+Fe. alpha-Tocopherol prevented both AA+Fe and AA+Fe+LY294002-induced toxicity and decrease of phosphorylated AKT. LY294002 potentiated AA+Fe-induced loss of mitochondrial membrane potential and ATP, whereas overexpression of constitutively active AKT partially prevented mitochondrial impairment and toxicity. Mitochondrial permeability transition inhibitors prevented both AA+Fe and AA+Fe+LY294002-induced toxicity and decrease of mitochondrial membrane potential. These results suggest that: i) AA+Fe+CYP2E1-induced oxidative stress decreases AKT activation; ii) AKT inactivation induces mitochondrial impairment associated with opening of the permeability transition pore but is not dependent on the activation state of bad, glycogen synthase kinase-3beta, mammalian target of rapamycin, or bcl-xL; and iii) PI3-kinase/AKT may serve as a survival pathway against CYP2E1-dependent toxicity. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16624972/Role_of_phosphatidylinositol_3_kinase/AKT_as_a_survival_pathway_against_CYP2E1_dependent_toxicity_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16624972 DB - PRIME DP - Unbound Medicine ER -