Geldanamycin, an inhibitor of Hsp90, potentiates cytochrome P4502E1-mediated toxicity in HepG2 cells

The Journal of Pharmacology and Experimental Therapeutics
Aparajita Dey, Arthur I Cederbaum

Abstract

Cytochrome P450 2E1 (CYP2E1) potentiates oxidative stress-mediated cell death. Heat shock proteins (Hsps) modulate the stability and function of numerous proteins. We examined the effect of geldanamycin (GA), an inhibitor of Hsp90, on CYP2E1-mediated toxicity in transfected HepG2 cells overexpressing CYP2E1 (E47 cells). Basal expression of CYP2E1 and Hsp90 was higher in E47 cells compared with control C34 cells, which do not express CYP2E1. Treatment with GA resulted in significant toxicity to E47 cells compared with C34 cells. An enhanced loss of E47 cell viability was also observed using two different inhibitors of Hsp90, herbimycin A and radicicol. Treatment of E47 cells with GA caused depletion of glutathione coupled to an increase in reactive oxygen species level and lipid peroxidation. These effects of GA were more pronounced in the E47 than the C34 cells. The antioxidants trolox and N-acetylcysteine prevented the increased reactive oxygen species accumulation and resultant loss of viability. GA caused increased caspase 3 activity and Annexin V staining in E47 cells, suggesting an apoptotic mode of cell death. A decrease in mitochondrial membrane potential was observed in GA-treated HepG2 cells, and mitochondrial permeabi...Continue Reading

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Citations

May 1, 2012·Cellular & Molecular Immunology·Samuel K ShimpChristopher M Reilly
Mar 23, 2012·Integrative Biology : Quantitative Biosciences From Nano to Macro·Karthikeyan ChandrasekaranAparajita Dey
Apr 27, 2010·Journal of Biomedical Science·Jia-Qi YaoJian-Min Li
May 31, 2014·Oxidative Medicine and Cellular Longevity·Mohamed A Abdelmegeed, Byoung-Joon Song
Jan 1, 2010·Cell Stress & Chaperones·Virginia L VegaAntonio De Maio
Nov 7, 2009·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Karthikeyan ChandrasekaranAparajita Dey
Feb 9, 2012·Alcoholism, Clinical and Experimental Research·Karthikeyan ChandrasekaranAparajita Dey
Jun 1, 2013·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Li WangWenhua Liu
Apr 24, 2014·European Journal of Nutrition·S Mathan KumarAparajita Dey

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