Genetic variation of basal iron status, ferritin and iron regulatory protein in mice: potential for modulation of oxidative stress.

Toxic and carcinogenic free radical processes induced by drugs and other chemicals are probably modulated by the participation of available iron. To see whether endogenous iron was genetically variable in normal mice, the common strains C57BL/10ScSn, C57BL/6J, BALB/c, DBA/2, and SWR were examined for major differences in their hepatic non-heme iron contents. Levels in SWR mice were 3- to 5-fold higher than in the two C57BL strains, with intermediate levels in DBA/2 and BALB/c mice. Concentrations in kidney, lung, and especially spleen of SWR mice were also greater than those in C57BL mice. Non-denaturing PAGE of hepatic ferritin from all strains showed a major holoferritin band at approximately 600 kDa, with SWR mice having > 3-fold higher levels than C57BL strains. SDS PAGE showed a band of 22 kDa, mainly representing L-ferritin subunits. A trace of a subunit at 18 kDa was also detected in ferritin from SWR mice. The 18 kDa subunit and a 500 kDa holoferritin from which it originates were observed in all strains after parenteral iron overload, and there was no major variation in ferritin patterns. Although iron uptake studies showed no evidence for differential duodenal absorption between strains to explain the variation in basal iron levels, acquisition of absorbed iron by the liver was significantly higher in SWR mice than C57BL/6J. As with iron and ferritin contents, total iron regulatory protein (IRP-1) binding capacity for mRNA iron responsive element (IRE) and actual IRE/IRP binding in the liver were significantly greater in SWR than C57BL/6J mice. Cytosolic aconitase activity, representing unbound IRP-1, tended to be lower in the former strain. SWR mice were more susceptible than C57BL/10ScSn mice to the toxic action of diquat, which is thought to involve iron catalysis. If extrapolated to humans, the findings could suggest that some people might have the propensity for greater basal hepatic iron stores than others, which might make them more susceptible to iron-catalysed toxicity caused by oxidants.

[1]  M. C. Ellis,et al.  A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis , 1996, Nature Genetics.

[2]  H. Clevers,et al.  Defective iron homeostasis in β2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man , 1997 .

[3]  B. Graubard,et al.  Moderate elevation of body iron level and increased risk of cancer occurrence and death , 1994, International journal of cancer.

[4]  M. Skolnick,et al.  Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. , 1988, The New England journal of medicine.

[5]  R. Simpson,et al.  Comparison of 59Fe3+ uptake in vitro and in vivo by mouse duodenum. , 1987, Biochimica et biophysica acta.

[6]  H. Dawson,et al.  Iron metabolism: a comprehensive review. , 2009, Nutrition reviews.

[7]  R. Popp,et al.  Spontaneous iron overload in alpha-thalassemic mice. , 1984, Blood.

[8]  Andrew G Smith,et al.  Interaction between iron metabolism and 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice with variants of the Ahr gene: a hepatic oxidative mechanism. , 1998, Molecular pharmacology.

[9]  D. Bumann,et al.  Influence of dietary iron overload on cell proliferation and intestinal tumorigenesis in mice. , 1992, Cancer letters.

[10]  R. Meneghini.  Iron homeostasis, oxidative stress, and DNA damage. , 1997, Free radical biology & medicine.

[11]  M. Hentze,et al.  Regulation of interaction of the iron-responsive element binding protein with iron-responsive RNA elements , 1989, Molecular and cellular biology.

[12]  R. Akhtar,et al.  Uroporphyria induced by 5-aminolaevulinic acid alone in Ahrd SWR mice. , 1996, Biochemical pharmacology.

[13]  S. Aust,et al.  Release of iron from ferritin and its role in oxygen radical toxicities. , 1988, Drug metabolism reviews.

[14]  Andrew G Smith,et al.  Iron as a synergist for hepatocellular carcinoma induced by polychlorinated biphenyls in Ah-responsive C57BL/10ScSn mice. , 1990, Carcinogenesis.

[15]  D. Reif,et al.  Ferritin as a source of iron for oxidative damage. , 1992, Free radical biology & medicine.

[16]  T. Peto,et al.  Characterization of ferritin in murine erythroleukaemia cells. , 1986, Biochimica et biophysica acta.

[17]  L. Kühn,et al.  Characterization of a second RNA-binding protein in rodents with specificity for iron-responsive elements. , 1993, The Journal of biological chemistry.

[18]  J. Salonen,et al.  Association between body iron stores and the risk of acute myocardial infarction in men. , 1998, Circulation.

[19]  F. Matteis.  Porphyria cutanea tarda of the toxic and sporadic varieties , 1998 .

[20]  R. Hider,et al.  Protoporphyria induced by the orally active iron chelator 1,2-diethyl-3-hydroxypyridin-4-one in C57BL/10ScSn mice. , 1997, Blood.

[21]  R. Leboeuf,et al.  Dissociation between tissue iron concentrations and transferrin saturation among inbred mouse strains. , 1995, The Journal of laboratory and clinical medicine.

[22]  W. H. Massover.  Molecular size heterogeneity of ferritin in mouse liver. , 1985, Biochimica et biophysica acta.

[23]  J. Cook,et al.  Iron metabolism in man , 1979 .

[24]  M. Hentze,et al.  Activation of iron regulatory protein-1 by oxidative stress in vitro. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Hentze,et al.  Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide, and oxidative stress. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Liehr,et al.  Enhancement of estrogen-induced renal tumorigenesis in hamsters by dietary iron. , 1998, Carcinogenesis.

[27]  P. Harrison,et al.  The ferritins: molecular properties, iron storage function and cellular regulation. , 1996, Biochimica et biophysica acta.

[28]  Bernstein Se.  Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia. , 1987 .

[29]  S. Jain,et al.  Ferritin synthesis in differentiating Friend erythroleukemic cells. , 1987, The Journal of biological chemistry.

[30]  A. K. Chan,et al.  Increased ferritin gene expression is associated with increased ribonucleotide reductase gene expression and the establishment of hydroxyurea resistance in mammalian cells. , 1990, The Journal of biological chemistry.

[31]  P. Sinclair,et al.  Role of small differences in CYP1A2 in the development of uroporphyria produced by iron and 5-aminolevulinate in C57BL/6 and SWR strains of mice. , 1999, Biochemical pharmacology.

[32]  H. Witschi,et al.  Ferritin and in vivo beryllium toxicity. , 1986, Toxicology and applied pharmacology.

[33]  H. Munro,et al.  Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5' untranslated region of ferritin heavy- and light-subunit mRNAs. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[34]  B. Cohen,et al.  A revised nomenclature for the mouse transferrin locus. , 1961 .

[35]  R. Simpson,et al.  Intestinal iron absorption studies in mouse models of iron‐overload , 1994, British journal of haematology.

[36]  W. Sly,et al.  HFE gene knockout produces mouse model of hereditary hemochromatosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[37]  H. Clevers,et al.  Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man , 1996, The Journal of experimental medicine.

[38]  S. Aust,et al.  The role of iron in oxygen-mediated toxicities. , 1992, Critical reviews in toxicology.

[39]  J. Salisbury,et al.  Tissue iron loading and histopathological changes in hypotransferrinaemic mice , 1993, The Journal of pathology.

[40]  L. Anderson,et al.  Promotion of dimethylbenz[a]anthracene-initiated mammary carcinogenesis by iron in female Sprague-Dawley rats. , 1997, Carcinogenesis.

[41]  M. Tancer,et al.  Iron homeostasis in beta-thalassemic mice. , 1987, Blood.