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ORIGINAL RESEARCH ARTICLE

Effects of gpx4 Haploid Insufficiency on GPx4 Activity, Selenium Concentration, and Paraquat-Induced Protein Oxidation in Murine Tissues

Michael S. Scimeca^*, Donald J. Lisk^*, Tomas Prolla and Xin Gen Lei^*,1

^* Department of Animal Science, Cornell University, Ithaca, New York 14853; and Department of Genetics, University of Wisconsin at Madison, Madison, Wisconsin 53706

To whom requests for reprints should be addressed at ¹ Cornell University, 252 Morrison Hall, Ithaca, NY 14853. E-mail: xl20{at}cornell.edu

Selenium-dependent glutathione peroxidase-4 (GPx4) catalyzes the reduction of phospholipid hydroperoxides. Because a full gpx4 knockout is embryonic lethal, we examined the effect of deletion of one copy of gpx4 on the activities of three selenoperoxidases (GPx1, GPx3, and GPx4), selenium concentrations, and pro-oxidant–induced protein oxidation in various tissues of mice. A total of 32 gpx4 hemizygous (GPx4^+/–) and wild-type (WT) mice (8- to 10-weeks old; 16 males and 16 females) were fed a selenium-adequate diet and given an intraperitoneal injection of paraquat (PQ; 24 mg/kg body wt) or phosphate-buffered saline (PBS). All mice were euthanized 4 hrs after injection to collect tissues for analyses. In PBS-treated mice, GPx4 activities in lung, liver, kidney, and testes of GPx4^+/– mice were 24–39% lower (P < 0.05) than in WT mice. Among PQ-treated mice, only testis GPx4 activity in GPx4^+/– mice was significantly lower (54% P < 0.05) than WT mice. Selenium concentration in testes, but not in other tissues, was reduced (34% P < 0.05) in GPx4^+/– mice compared with WT mice, irrespective of treatment. Tissue GPx1 activities and plasma GPx3 and alanine aminotransferase (ALT) activities were unaffected by PQ treatment or gpx4 hemizygosity. Total protein carbonyl was elevated (73% P < 0.05) by PQ only in lung, and this effect of PQ was independent of genotypes. In conclusion, gpx4 haploid insufficiency reduced GPx4 activities and/or selenium concentrations, but had no effect on pro-oxidant–induced protein oxidation in various tissues of mice.

Key Words: oxidative stress • paraquat • phospholipid hydroperoxide • glutathione peroxidase • gpx4 • hemizygous • selenium