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ToxSci Advance Access published online on September 1, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh268
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received July 22, 2004
Accepted August 23, 2004

Biotransformation and Toxicokinetics

Analyses of Glutathione Reductase Hypomorphic Mice Indicate a Genetic Knock-Out

Lynette K. Rogers 1*, Toshiya Tamura 1, Bryan J. Rogers 1, Stephen E. Welty 1, Thomas N. Hansen 1, Charles V. Smith 1

1 Center for Developmental Pharmacology and Toxicology, Children's Research Institute, Columbus, Ohio 43205

* To whom correspondence should be addressed. E-mail: rogersl{at}chi.osu.edu.


  Abstract

A strain of mice (Gr1a1Neu) that exhibited tissue glutathione reductase (GR) activities that were substantially lower (less than 10% in liver) than the corresponding activities in control mice (Pretsch, 1999) has been reported. The present report describes characterization of the mutation(s) in the GR gene of these mice. RT-PCR of mRNA from the Neu mice indicated a substantial deletion in the normal GR coding sequence. Southern blots revealed that the deletion involved a region spanning from intron 1 through intron 5. The exact breakpoints of the deletion were characterized by PCR and sequencing through the region encompassing the deletion. The deletion involves nucleotides 10840 through 23627 of the genomic GR gene and functionally deletes exons 2 through 5. In addition, the deletion produces a frame shift in exon 6 and introduces a stop codon in exon 7 that would prevent translation of the remainder of the protein. Consequently, the Neu mice are incapable of producing a functional GR protein and appear to be genetic knock-outs for GR. The Neu mice offer live animal models with which to test hypotheses regarding oxidant mechanisms of tissue injury in vivo.

Keywords: glutathione reductase; knockout.
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