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.
Clothier
B
B
MRC Toxicology Unit, University of Leicester, U.K.
Robinson
S
S
Akhtar
R A
RA
Francis
J E
JE
Peters
T J
TJ
Raja
K
K
Smith
A G
AG
D000042:Absorption; D000818:Animals; D004178:Diquat / Q000633:toxicity; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D014644:Genetic Variation; D006540:Herbicides / Q000633:toxicity; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019159:Nonheme Iron Proteins; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity
D006540:Herbicides; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D019159:Nonheme Iron Proteins; D016601:RNA-Binding Proteins; D005293:Ferritins; D004178:Diquat; D007501:Iron; D035941:Iron Regulatory Protein 1