|South, Paul - FDA|
Submitted to: Biological Trace Element Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: February 28, 2002
Publication Date: July 1, 2002
Citation: South, P., Levander, O.A., Smith, A.D. 2002. Effects of dietary iron overload on glutathione peroxidase knock-out mice. Biological Trace Element Research. Interpretive Summary: Excess iron intake has been associated with an increased risk of heart disease in humans. Previous work by us has shown that feeding a high-iron diet to selenium -deficient mice for 4 weeks resulted in elevated plasma cholesterol and triglyceride levels and increased damage to fats in the liver. Here we report the effect of dietary iron overload in mice lacking an important antioxidant enzyme, glutathione peroxidase (GPX-KO mice), that requires selenium for its activity. Normal mice or GPX-KO mice were fed either an iron-adequate or high-iron diet for 4 weeks. Although liver iron was elevated in mice fed the high-iron diet, damage to liver fats was not seen in either normal or GPX-KO mice on either diet. Moreover, plasma cholesterol was not elevated in the Fe-overloaded GPX1 KO mice. Thus, decreased enzyme activity in the GPX-KO mice cannot account for the high cholesterol effects observed earlier in mice fed the high-iron selenium-deficient diet. This suggests selenium exerts its effect on cholesterol and liver fats in the iron overloaded selenium-deficient mice by some way other than affecting glutathione peroxidase activity.
Technical Abstract: Excess iron (Fe) intake has been associated with an increased risk of cardiovascular disease in humans, presumably due to increased oxidative stress. Previous work by us has shown that feeding a high-Fe diet to selenium (Se)-deficient weanling mice for 4 weeks resulted in elevated plasma cholesterol and triglycerides and increased hepatic thiobarbituric acid reactive substances (TBARS). Here we report the effect of Fe overload in mice lacking cellular glutathione peroxidase (GPX1 knock-out (KO) mice), the selenoenzyme thought to account for much of the antioxidant action of Se. Weanling wild type (WT) or GPX1 KO mice were fed either an Fe-adequate (35 ppm Fe) or high-Fe (1100 ppm Fe) casein-based diet for 4 weeks. Iron was added as ferric citrate. Both diets also contained 0.2 ppm Se added as sodium selenite. As expected, liver GPX1 activity was essentially absent in the KO mice. Another Se parameter measured (hepatic thioredoxin reductase activity) did not vary across groups. Although liver Fe was elevated in mice fed the high-Fe diet, liver TBARS was largely unaffected either by mouse genotype or diet fed. Moreover, plasma lipids were not elevated in the Fe-overloaded GPX1 KO mice. Thus, decreased GPX1 activity cannot account for the pro-oxidant hyperlipidemic effects observed earlier in mice fed the high-Fe Se-deficient diet. This suggests that impairment of Se functions other than GPX1 activity may be responsible for the elevated plasma lipids and hepatic TBARS seen in the Fe overloaded Se-deficient mice.