Characterization and accumulation of ferritin in hepatocyte nuclei of mice with iron overload.
After a single subcutaneous dose of iron-dextran (600 mg of iron/kg), iron overload developed in C57BL/10ScSn mice. At 4, 24 and 78 wk liver nonheme iron concentrations were 67-, 42- and 21-fold higher than controls, respectively. Much of the iron was in macrophages, but hepatocytes were also strongly positive for Perls' stainable iron. One feature was the development of iron-positive nuclear inclusions in hepatocytes. After a delay of at least 8 wk when no stainable iron was evident, a maximum of 37% of periportal hepatocytes contained inclusions by 24 wk. Although this proportion remained constant for the remainder of the study, the size of the inclusions (which were not membrane-limited) increased to greater than 3 microns in diameter, occupying greater than 25% of the nuclear volume. The presence of iron in the inclusions was confirmed by energy dispersive x-ray microanalysis. Immunocytochemical studies showed that the iron was present as aggregates of ferritin. Quantitation of nonaggregated ferritin molecules by image analyses after electron microscopy demonstrated that within 4 wk ferritin levels in cytoplasm and nucleoplasm had greatly increased but that there was a concentration gradient of approximately one order of magnitude across the nuclear envelope. These findings are consistent with the hypothesis that in iron-loaded mouse hepatocytes there is a slow passage of ferritin-molecules through the nuclear pores; the gradient is maintained by the continual aggregation of ferritin within the nucleus. Intranuclear ferritin may provide a source of iron for catalyzing hydroxyl radical formation in nuclei during some toxic, carcinogenic and aging processes.
Smith
A G
AG
MRC Toxicology Unit, Carshalton, Surrey, United Kingdom.
Carthew
P
P
Francis
J E
JE
Edwards
R E
RE
Dinsdale
D
D
D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry; D004577:Electron Probe Microanalysis; D005293:Ferritins / Q000032:analysis*; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D007501:Iron / Q000378:metabolism*; D007505:Iron-Dextran Complex / Q000008:administration & dosage / Q000493:pharmacokinetics; D007728:Kupffer Cells / Q000737:chemistry; D008099:Liver / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008247:Lysosomes / Q000737:chemistry; D008264:Macrophages / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D010588:Phagosomes / Q000737:chemistry; D010758:Phosphorus / Q000032:analysis
D010758:Phosphorus; D007505:Iron-Dextran Complex; D005293:Ferritins; D007501:Iron