Skip Navigation


ToxSci Advance Access originally published online on May 5, 2004
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
80/2/350    most recent
kfh160v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (4)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Dong, J.
Right arrow Articles by Monks, T. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dong, J.
Right arrow Articles by Monks, T. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Toxicological Sciences 80, 350-357 (2004)
Toxicological Sciences vol. 80 no. 2 © Society of Toxicology 2004; all rights reserved.

Induction of ERK1/2 and Histone H3 Phosphorylation within the Outer Stripe of the Outer Medulla of the Eker Rat by 2,3,5-Tris-(Glutathion-S-yl)hydroquinone

Jing Dong*,{dagger}, Jeffrey I. Everitt{ddagger}, Serrine S. Lau* and Terrence J. Monks*,1

* Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona Health Sciences Center, Tucson, Arizona 85721; {dagger} Department of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712; and {ddagger} GlaxoSmithKline, Research Triangle Park, North Carolina 27709

Received February 28, 2004; accepted April 20, 2004

2,3,5-tris-(glutathion-S-yl)-hydroquinone (TGHQ), a metabolite of hydroquinone (HQ), generates reactive oxygen species (ROS) in cultured renal epithelial cells and binds to tissue macromolecules within the rat kidney. The potential mechanisms by which TGHQ induces nephrotoxicity and nephrocarcinogenesis have been examined in cell culture models, but less is known concerning the molecular mechanisms of TGHQ-induced nephrotoxicity in vivo. In LLC-PK1 cells, TGHQ induces phosphorylation of both mitogen-activated protein kinase and histone H3, which likely promotes inappropriate chromatin condensation and mitotic catastrophe. Using the Eker (Tsc-2 mutant) rat as a model, we show by immunohistochemistry that TGHQ (7.5 µmol/kg) selectively induces ERK1/2 phosphorylation within the outer stripe of the outer medulla (OSOM) of the kidney. ERK1/2 phosphorylation is time-dependant, occurring as early as 1 h following treatment, and reaching maximal levels by 4 h. Subsequently, ERK1/2 phosphorylation returns to baseline levels by 24 h post treatment. ERK1/2 phosphorylation was confirmed by western blot analysis of OSOM tissue. Increases in histone H3 phosphorylation occurred subsequent to ERK1/2 phosphorylation (8 h), and reached a peak by 24 h, coincident with histological evidence of tissue necrosis. In contrast to studies in cell culture, neither JNK/SAPK nor p38 MAPK phosphorylation were significantly altered after TGHQ administration in vivo, as evidenced by western blot and immunohistochemical analyses. These data indicate that activation of the ERK1/2 pathway precedes overt cytotoxicity and that the signaling pathways activated by TGHQ in vivo and in vitro differ.

Key Words: TGHQ; MAPK; histone H3; Eker rats; ROS.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
G. K. Scott, C. Atsriku, P. Kaminker, J. Held, B. Gibson, M. A. Baldwin, and C. C. Benz
Vitamin K3 (Menadione)-Induced Oncosis Associated with Keratin 8 Phosphorylation and Histone H3 Arylation
Mol. Pharmacol., September 1, 2005; 68(3): 606 - 615.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.