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ToxSci Advance Access published online on May 5, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh160
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received February 28, 2004
Accepted April 20, 2004

Systems Evaluation

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 1, Jeffrey Everitt 2, Serrine S. Lau 3, Terrence J. Monks 3*

1 Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona Health Sciences Center, Tucson, Arizona 85721; Department of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712
2 GlaxoSmithKline, Research Triangle Park, North Carolina 27709
3 Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona Health Sciences Center, Tucson, Arizona 85721

* To whom correspondence should be addressed. E-mail: Scouser{at}pharmacy.arizona.edu.


  Abstract

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 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, 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 analysis. These data indicate that activation of the ERK1/2 pathway and subsequent histone H3 phosphorylation precede 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 .


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