Please use this identifier to cite or link to this item: https://doi.org/10.1093/toxsci/kfm273
Title: The mitochondrial superoxide/thioredoxin-2/ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes
Authors: Lim, P.I.K.
Liu, J.
Go, M.I. 
Boelsterli, U.A.
Keywords: Idiosyncratic drug toxicity
Mito-CP
Mitochondria
Oxidative stress
Thioredoxin-2
Troglitazone
Issue Date: Feb-2008
Citation: Lim, P.I.K., Liu, J., Go, M.I., Boelsterli, U.A. (2008-02). The mitochondrial superoxide/thioredoxin-2/ask1 signaling pathway is critically involved in troglitazone-induced cell injury to human hepatocytes. Toxicological Sciences 101 (2) : 341-349. ScholarBank@NUS Repository. https://doi.org/10.1093/toxsci/kfm273
Abstract: Although the mechanisms and susceptibility factors of troglitazone-associated idiosyncratic liver injury have not been elucidated, experimental evidence has identified oxidant stress and mitochondrial injury as a potential hazard in vitro. In search of upstream mediators of toxicity, we hypothesized that troglitazone-induced increased mitochondrial generation of superoxide might activate the thioredoxin-2 (Trx2)/apoptosis signal-regulating kinase 1 (Ask1) signaling pathway, leading to cell death, and that, hence, the mitochondrially targeted radical scavenger, mito-carboxy proxyl (CP), would prevent the increase in superoxide net levels and inhibit mitochondrial signaling and cell injury. Immortalized human hepatocytes (HC-04) were exposed to troglitazone (0-100μM), which caused concentration and time-dependent apoptosis after 12-24 h (ketoconazole-insensitive). We found that troglitazone rapidly dissipated the mitochondrial inner transmembrane potential (ΔΨm) and independently increased the net levels of mitochondrial superoxide by 5-fold. This was followed by a shift of the redox ratio of mitochondrial Trx2 toward the oxidized state and subsequent activation of Ask1. Cell injury, but not the decrease in ΔΨm, was prevented by cyclosporin A (3μM), indicating that mitochondrial permeabilization, but not membrane depolarization, was causally involved in cell death. Mito-CP not only decreased troglitazone-induced superoxide levels but also prevented Trx2 oxidation and activation of Ask1 and protected cells from toxic injury. These data indicate that troglitazone, but not its oxidative metabolite(s), produce intramitochondrial oxidant stress that activates the Trx2/Ask1 pathway, leading to mitochondrial permeabilization. Furthermore, the data support our concept that targeted delivery of an antioxidant to mitochondria can inhibit upstream signaling and protect from troglitazone-induced lethal cell injury. © The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
Source Title: Toxicological Sciences
URI: http://scholarbank.nus.edu.sg/handle/10635/106443
ISSN: 10966080
DOI: 10.1093/toxsci/kfm273
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

47
checked on May 26, 2018

WEB OF SCIENCETM
Citations

43
checked on Mar 14, 2018

Page view(s)

38
checked on May 25, 2018

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.