Deletion of selenoprotein P upregulates urinary selenium excretion and depresses whole-body selenium content

Abstract

Deletion of the mouse selenoprotein P gene (Sepp1) lowers selenium concentrations in many tissues. We examined selenium homeostasis in Sepp1(-/-) and Sepp1(+/+) mice to assess the mechanism of this. The liver produces and exports selenoprotein P, which transports selenium to peripheral tissues, and urinary selenium metabolites, which regulate whole-body selenium. At intakes of selenium near the nutritional requirement, Sepp1(-/-) mice had whole-body selenium concentrations 72 to 75% of Sepp1(+/+) mice. Genotype did not affect dietary intake of selenium. Sepp1(-/-) mice excreted in their urine approximately 1.5 times more selenium in relation to their whole-body selenium than did Sepp1(+/+) mice. In addition, Sepp1(-/-) mice gavaged with (75)SeO(2-)(3) excreted 1.7 to 2.4 times as much of the (75)Se in the urine as did Sepp1(+/+) mice. These findings demonstrate that deletion of selenoprotein P raises urinary excretion of selenium. When urinary small-molecule (75)Se was injected intravenously into mice, over 90% of the (75)Se appeared in the urine within 24 h, regardless of selenium status. This shows that urinary selenium is dedicated to excretion and not to utilization by tissues. Our results indicate that deletion of selenoprotein P leads to increased urinary selenium excretion. We propose that the absence of selenoprotein P synthesis in the liver makes more selenium available for urinary metabolite synthesis, increasing loss of selenium from the organism and causing the decrease in whole-body selenium and some of the decreases observed in tissues of Sepp1(-/-) mice.

Scheme 1

Relationships of “metabolically active” selenium pool in the liver with synthesis of selenoproteins and urinary selenium metabolites.

Figure 1

Whole-body selenium concentration in Sepp1^−/− (open bars) and Sepp1^+/+ (shaded bars) mice. Mice were fed the respective diets as follows: The 0.1 mg selenium/kg group (Sepp1^−/− mice weight 15.5 ± 0.7 g, n=6; Sepp1^+/+ mice weight 20.8 ± 0.9 g, n=7) was fed the 0.25 mg selenium/kg diet for 2 weeks from weaning and then switched to the 0.1 mg selenium/kg diet for 2 weeks before being studied. This was done because Sepp1^−/− mice develop nervous system injury if fed the 0.1 mg selenium/kg diet immediately after weaning [14]. The group fed 0.25 mg selenium/kg diet from weaning (Sepp1^−/− mice weight 20.2 ± 1.7 g, n=9; Sepp1^+/+ mice weight 22.6 ± 1.0 g, n=10) was fed the diet for 4 weeks. At the time of study, selenium was determined in selected tissues and in the rest of the carcass. Values shown are sums of all body parts. They are means ± S.D. Asterisks indicate pairs that were significantly different (P<0.05) by the Student t-test.

Figure 2

Urinary ⁷⁵Se excretion by Sepp1^−/− (open bars) and Sepp1^+/+ (shaded bars) mice administered ⁷⁵SeO₃²⁻ by gavage. Mice were fed the respective diets as described in the legend to figure 1. They were then gavaged and urine was collected for 24 hours in plastic metabolic cages. Values are means ± S.D., n=4-8. Asterisks indicate pairs that were significantly different (P<0.05) by the Student t-test.

Figure 3

Urinary ⁷⁵Se excretion by selenium deficient and control mice administered ⁷⁵Se-labeled selenite or ⁷⁵Se-labeled urinary metabolite by tail vein. The amount of selenium administered to each mouse was 8.8 ng. After injection, mice were put into metabolic cages and urine was collected for 24 hours. The results shown are percentages of the total recovered ⁷⁵Se that was in the urine. Values are means ± S.D., n=4-8. Excretions by the groups given ⁷⁵Se-labeled selenite were significantly different (P<0.05) from one another by the Student t-test.