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 ch emicals are probably modulated by the participation of available iron. To s ee whether endogenous iron was genetically variable in normal mice, the com mon strains C57BL/10ScSn, C57BL/6J, BALB/c, DBA/2, and SWR were examined fo r 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 intermedi ate levels in DBA/2 and BALB/c mice. Concentrations in kidney, lung, and es pecially spleen of SWR mice were also greater than those in C57BL mice. Non -denaturing PAGE of hepatic ferritin from all strains showed a major holofe rritin band at approximately 600 kDa, with SWR mice having >3-fold higher l evels than C57BL strains. SDS PAGE showed a band of 22 kDa, mainly represen ting 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 fr om which it originates were observed in all strains after parenteral iron o verload, and there was no major variation in ferritin patterns. Although ir on uptake studies showed no evidence for differential duodenal absorption b etween strains to explain the variation in basal iron levels, acquisition o f absorbed iron by the liver was significantly higher in SWR mice than C57B L/6J. As with iron and ferritin contents, total iron regulatory protein (IR P-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 m ice. Cytosolic aconitase activity, representing unbound IRP-1, tended to be lower in the former strain. SWR mice were more susceptible than C57BL/10Sc Sn mice to the toxic action of diquat, which is thought to involve iron cat alysis. Ii extrapolated to humans, the findings could suggest that some peo ple might have the propensity for greater basal hepatic iron stores than ot hers, which might make them more susceptible to iron-catalysed toxicity cau sed by oxidants. BIOCHEM PHARMACOL 59;2:115-122, 2000. (C) 1999 Elsevier Sc ience Inc.