The Journal of Nutrition Vol. 127 No. 8 August 1997, pp. 1445-1450
Copyright ©1997 by the American Society for Nutritional Sciences

Cellular Glutathione Peroxidase Knockout Mice Express Normal Levels of Selenium-Dependent Plasma and Phospholipid Hydroperoxide Glutathione Peroxidases in Various Tissues

Manuscript received 6 February 1997. Initial reviews completed 17 March 1997. Revision accepted 24 April 1997.

Wen-Hsing Cheng^*, Ye-Shih Ho, Deborah A. Ross^*, Beth A. Valentine^**, Gerald F. Combs Jr., and Xin Gen Lei^*,

Departments of ^* Animal Science and ^** Pathology and  Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853 and  Institute of Chemical Toxicology, Wayne State University, Detroit, MI 48201

Selenium-dependent cellular glutathione peroxidase (GPX1) knockout [GPX1()] mice were derived from 129/SVJ × C57BL/6 hybrid mice by microinjecting C57BL/6 blastocysts with recombinant embryonic stem cells carrying a target mutation in the GPX1 gene. Experiment 1 was conducted to determine the effects of the GPX1 knockout on the susceptibility of mice to dietary vitamin E and Se deficiency and on the expression of the Se-dependent plasma glutathione peroxidase (GPX3) and phospholipid hydroperoxide glutathione peroxidase (GPX4), and the Se-independent glutathione S-transferase (GST). Eleven GPX1() and 11 control mice (5 wk old, six males and five females) were fed a Se-deficient, Torula yeast basal diet (0.02 mg Se/kg, no supplemental vitamin E) or the basal diet supplemented with 0.5 mg Se/kg (as Na₂SeO₃) for 13 wk. Experiment 2 was conducted to determine the effect of the GPX1 knockout on the total Se concentration in the liver of Se-adequate mice. Six GPX1() and four control mice (5 wk old, half males and females) were fed the basal diet supplemented with 0.2 mg Se/kg and 15 mg of all-rac--tocopheryl acetate/kg for 5 wk. There was no difference in body weight gain or apparent susceptibility to dietary vitamin E and Se deficiency between the GPX1() and control mice. Knockout of GPX1 resulted in almost complete abolishment of GPX1 activity in various tissues, but had no effect on the GPX3 or GPX4 mRNA level and activity or the GST activity in several tissues at either level of dietary Se. The liver total Se concentration in the Se-adequate GPX1() mice was only 42% of that in the controls (P < 0.0001). These results indicate that GPX1 is expressed independently of GPX3 or GPX4 and represents ~60% of the total hepatic Se in Se-adequate mice.

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