Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following the subchronic intoxication of rats with phenylhydrazine, resulting in marked anemia, reticulocytosis, methemoglobinemia and increased hemocatheresis, the hepatic content of total iron was increased, as was hepatic ferritin and its saturation by iron. A striking increase (approximately 7-fold) was also observed in free iron which appeared to be redox-active. The increase in liver free iron involved the hepatocellular component of the liver. Since DNA is one of the cellular targets of redox active iron, liver DNA from phenylhydrazine-treated rats was analyzed by electrophoresis and found to be markedly fragmented. Experiments with isolated hepatocytes in culture or in suspension challenged with phenylhydrazine or Fe-nitrilotriacetate strongly suggested that the DNA damage was due to reactive iron rather than to the hepatic metabolism of phenylhydrazine. The levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), a specific marker of oxidative DNA damage, were significantly higher in phenylhydrazine-treated rats as compared to untreated controls. The prolongation of phenylhydrazine treatment over a period of 6 weeks resulted in a persistent damage to DNA and in phenotypic changes such as an increase in hepatocyte gamma-glutamyl transpeptidase (gamma-GT, EC 2.3.2.2) activity. Possible relationships between iron overload, iron release, DNA damage and tumor initiation are discussed.
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PMID:Release of free, redox-active iron in the liver and DNA oxidative damage following phenylhydrazine intoxication. 926 28

Estrogens induce hydroxyl radical-mediated DNA and protein damage and lipid peroxidation. As part of a study of the mechanism of hydroxyl radical generation by estrogens, we investigated the in vitro mobilization of Fe2+ from ferritin by redox cycling of the stilbene or steroid estrogen metabolites diethylstilbestrol-4',4"-quinone (DESQ), equilenin-3,4-quinone (EQ), or estrone-3,4-quinone (3,4EQ). Aerobic cytochrome P450 reductase-mediated redox cycling of 35.50 microM DESQ, 0.35 microM EQ, or 3.55 microM 3,4EQ increased the reduction of succinoylated cytochrome c, a measure of superoxide radical formation, by 19-20% over control values (24.5+/-0.3 microM) in the absence of estrogen quinone substrate. Rates of Fe2+ release from horse spleen ferritin by cytochrome P450 reductase-mediated redox cycling of 35.50 microM DESQ, 0.35 microM EQ, or 3.55 microM 3,4EQ were 94.4+/-0.6, 117.2+/-9.4, or 137.7+/-19.9 pmol Fe2+/min, respectively, compared to 67.3 + 2.3 pmol Fe2+/min in the absence of estrogen substrates. Redox cycling of 35.5 microM DESQ, EQ, or 3,4EQ mediated by microsomes of hamster kidney, a target organ of estrogen-induced carcinogenesis, released 511+/-30.10, 516.91+/-22.90, or 410.27+/-28.49 pmol Fe2+/min, respectively. Corresponding values with microsomes of hamster liver, where tumors do not develop by estrogen treatment, were 272.27+/-43.10, 222.25+/-21.78, or 91.36+/-8.54 pmol Fe2-/min, respectively. Diethylstilbestrol, equilenin, and 4-hydroxyestrone do not induce detectable iron release from ferritin under these conditions. The cytochrome P450 reductase-mediated redox cycling of DESQ, EQ, or 3,4EQ in the presence of iron resulted in the hydroxylation of benzoic acid by hydroxyl radical attack. These data demonstrate that redox cycling of estrogen metabolites releases Fe2+ from ferritin, which in turn generates hydroxyl radicals by a Fenton reaction. This estrogen-induced hydroxyl radical damage may contribute to tumor initiation in hormone target tissues, including breast cancer.
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PMID:Release of iron from ferritin storage by redox cycling of stilbene and steroid estrogen metabolites: a mechanism of induction of free radical damage by estrogen. 934 64