Rinsho Ketsueki. 1989 Aug;30(8):1115-27. Related Articles, Links
[Pathogenesis and mechanism of iron overload: ferric nitrilotriacetate,
hemosiderin, active oxygen, and carcinogenesis]
[Article in Japanese]
Awai M.
Iron overload is found clinically in such conditions as hemochromatosis
and sideroblastic anemia, and after long term repeated transfusion in
aplastic anemia. An animal model of iron overload was successfully
developed in rats and rabbits by repeated intraperitoneal injections of
ferric nitrilotriacetate (Fe3+-NTA). This procedure induced a diabetic
state with hyperglycemia, ketonemia, glycosuria and ketonuria. Blood
venesection on these rats reduced the iron load in the liver and
pancreas, and ameliorated the general diabetic symptoms. A single
injection of Fe3+-NTA in rats induced a temporary elevation in plasma
iron concentration, lipid peroxidation in the perfused liver homogenate
expressed by malondialdehyde (MDA) formation, blood GOT, GPT, ALP and
gamma-GTP sequentially. Fe3+-NTA uptake in the liver caused membrane
lipid peroxidation, and subsequently produced a transit liberation of
liver cell enzymes, although the incorporated liver Fe3+-NTA was only
1% of the injected dosage (7.5 mg iron/kg BW) at 3 hr after injection.
The direct toxic effect of Fe3+-NTA to living cells was examined using
cultured normal rat liver parenchymal cells (RL-34). Marked cytolysis
was found in cells exposed to more than 25 micrograms of iron through
Fe3+-NTA/ml. At 50 micrograms iron of Fe3+-NTA/ml, most cells were
lethally injured and the remaining cells were piled up and aggregated
at 15 days. They grew on soft agar culture, and when inoculated
subcutaneously to five newly born rats a subcutaneous tumor developed
in all animals within three weeks. Lung metastases were found in three
of five inoculated rats. A spin trapping technique with electron spin
resonance (ESR) on Fe3+-NTA employing 5, 5-dimethyl-l-pyrroline-N-oxide
(DMPO) yielded a spin adduct with three doublets (DMPO-Z) which
corresponded to singlet oxygen. By ESR in the presence of H2O2, the
Fe3+-NTA solution strongly generated hydroxyl radical. The production
of active oxygen species by Fe3+-NTA solution may explain the toxicity
and carcinogenicity of Fe3+-NTA. The majority of stainable iron in the
iron overloaded tissue was hemosiderin (Hs). We tried to purify the Hs
from multi-transfused human spleen by the method of Weir et al. The
purified Hs did not show a DMPO-OH adducts in the presence of H2O2 and
DMPO on ESR measurement. The Hs iron was solubilized with several
biological ligands in an acidic state in the presence of a reducing
reagent like glutathione. Solubilized Hs iron produced iron chelate
complexes which resulted in OH radicals production in the presence of
H2O2 in acidic conditions below pH 5.5.(ABSTRACT TRUNCATED AT 400
WORDS)
Publication Types:
Review
Review, Tutorial
PMID: 2689676 [PubMed - indexed for MEDLINE]
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