The mobilization of ferritin iron by liver cytosol. A comparison of xanthine and NADH as reducing substrates

Topham, Richard W.; Goger, M; Pearce, Kenneth H.; Schultz, Pamela J.

doi:10.1042/bj2610137

Cited by 48 publications

(20 citation statements)

References 28 publications

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“…P<0.05 to all other groups. Fellman & Raivio 1997) and that NADH or NADPH can serve as reducing co-factors for the enzyme-mediated reduction of ferritin iron (Topham et al 1989;Jaeschke et al 1992). Flavin nucleotide has been suggested to shuttle the electrons to the ferritin iron (Topham et al 1989).…”

Section: Discussionmentioning

confidence: 98%

“…Fellman & Raivio 1997) and that NADH or NADPH can serve as reducing co-factors for the enzyme-mediated reduction of ferritin iron (Topham et al 1989;Jaeschke et al 1992). Flavin nucleotide has been suggested to shuttle the electrons to the ferritin iron (Topham et al 1989). The release of iron from ferritin can be due to direct reduction of iron by NADH/NADPH, or can be mediated by superoxide radical generated by NADH/NADPH dependent enzymes (Bando & Aki 1990).…”

Section: Discussionmentioning

confidence: 98%

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Combination of Iron Overload Plus Ethanol and Ischemia Alone Give Rise to the Same Endogenous Free Iron Pool

et al. 2005

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Iron overload aggravates tissue damage caused by ischemia and ethanol intoxication. The underlying mechanisms of this phenomenon are not yet clear. To clarify these mechanisms we followed free iron ("loosely" bound redox-active iron) concentration in livers from rats subjected to experimental iron overload, acute ethanol intoxication, and ex vivo warm ischemia. The levels of free iron in non-homogenized liver tissues, liver homogenates, and hepatocyte cultures were analyzed by means of EPR spectroscopy. Ischemia gradually increased the levels of endogenous free iron in liver tissues and in liver homogenates. The increase was accompanied by the accumulation of lipid peroxidation products. Iron overload alone, known to increase significantly the total tissue iron, did not affect either free iron levels or lipid peroxidation. Homogenization of iron-loaded livers, however, resulted in the release of a significant portion of free iron from endogenous depositories. Acute ethanol intoxication increased free iron levels in liver tissue and diminished the portion of free iron releasing during homogenization. Similarly to liver tissue, the primary hepatocyte culture loaded with iron in vitro released significantly more free iron during homogenization compared to non iron-loaded hepatocyte culture. Analyzing three possible sources of free iron release under these experimental conditions in liver cells, namely ferritin, intracellular transferrin-receptor complex and heme oxygenase, we suggest that redox active free iron is released from ferritin under ischemic conditions whereas ethanol and homogenization facilitate the release of iron from endosomes containing transferrin-receptor complexes.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Combination of Iron Overload Plus Ethanol and Ischemia Alone Give Rise to the Same Endogenous Free Iron Pool

et al. 2005

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“…Ferritin plays a key role in the iron metabolism of mammalian cells, so that the iron it stores in ferritin is reductively mobilized as needed for the synthesis of iron-containing proteins (6). NAD(P)H can serve as a source of reducing power for the enzyme-mediated reduction and mobilization of ferritin iron (24). In addition, a transit iron pool composed of iron chelated by ATP has also been found in reticulocytes (26).…”

Section: Measurement Of H2s Productionmentioning

confidence: 99%

Roles of ATP and NADPH in Formation of the Fe-S Cluster of Spinach Ferredoxin

Takahashi¹,

Mitsui²,

Fujita³

et al. 1991

Plant Physiol.

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Ferredoxin (Fd) in higher plants is encoded by a nuclear gene, synthesized in the cytoplasm as a larger precursor, and imported into the chloroplast, where it is proteolytically processed, and assembled with the (2Fe-2S] cluster. The final step in the biosynthetic pathway of Fd can be analyzed by a reconstitution system composed of isolated chloroplasts and [35SJcysteine, in which [35S]sulfide and iron are incorporated into Fd to build up the 35S-labeled Fe-S cluster. Although a lysed chloroplast system shows obligate requirements for ATP and NADPH, in vitro chemical reconstitution of the Fe-S cluster is generally thought to be energy-independent. The present study investigated whether ATP and NADPH in the chloroplast system of spinach (Spinacia Recent progress in the field of molecular biology has made it possible to clone the genes for Fe-S proteins from a wide variety of materials and express them in foreign hosts such as Escherichia coli. The Bacillus subtilis gene encoding glutamine phosphoribosylpyrophosphate amidotransferase has been cloned and expressed in E. coli (13). The Bacillus enzyme was functionally expressed in E. coli after correct processing in two steps; the removal of 11 amino acid residues from the amino-terminus, and assembly of the [4Fe-4S] cluster into its polypeptide. Genes encoding [2Fe-2S] proteins, human adrenodoxin, and cyanobacterial Fds have also been expressed in E. coli, and the [2Fe-2S] clusters were assembled and incorporated into Fds in these heterogeneous systems (2, 4). The correct assembly of Fe-S clusters into foreign proteins suggests several possibilities for in vivo cluster formation. The Fe-S cluster may be assembled spontaneously from apoprotein, sulfide, and iron by a mechanism similar to that reported in earlier in vitro chemical reconstitutions (14, 16). Alternatively, unknown enzymes may be involved in the assembly process. If the assembly is enzymatic, the enzymes responsible must have broad specificity for protein acceptors, or are involved in preassembly of the Fe-S cluster moiety followed by its spontaneous incorporation into apoprotein. It should also be noted that the expression of active nitrogenase iron protein (nill-encoded) in E. coli requires expression of an additional gene (nijM) (10), suggesting that the niJtI product alone is insufficient for assembly of the [4Fe-4S] cluster in a foreign host.We have addressed this problem and reported physiological formation of the Fe-S cluster in isolated intact and hypotonically lysed spinach chloroplasts (21,22

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“…Clinical observations point at a synergistic hepatotoxic effect from the combination of iron and alcohol [61,64], In vitro experiments indicate that this synergism may be attributed to increased lipid peroxidation, mediated by alcohol-induced redox changes that mobilize free iron ions from ferritin [65,66], Using an animal model in which feeding with dietarycarbonyl iron was combined with a liquid eth anol diet, iron and ethanol in combination produced a marked elevation of plasma ami notransferases, compared with either sub stance alone ( fig. 4a) [14], The combination also led to development of spotty necrosis in the liver parenchyma.…”

Section: Iron-induced Damage O F Hepatocytesmentioning

confidence: 99%

Iron as a Hepatotoxin

Stål¹

1995

Dig Dis

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Although essential for life, iron in excessive amounts may be toxic. The liver is particularly subject to the toxic effects of iron, since it is the major site of iron storage. Several inherited and acquired human disorders may result in hepatic iron overload, the most common of which are genetic hemochromatosis (GH) and transfusional iron overload. GH is an inherited disorder of iron metabolism, and in patients with GH excess iron absorbed from the gut is transported through the portal vein to the liver. The mechanisms by which excess iron exerts its cytotoxic effects include enhanced formation of free radicals and peroxidation of organelle membrane lipids. Lipid peroxidation can lead to structural and functional alterations in lysosomes, mitochondria and the endoplasmic reticulum. With massive iron overload, such iron-induced alterations may cause cell death, also known as sideronecrosis. At this stage, fibrogenesis is initiated and, if the excess iron is not removed, the increased deposition of collagen progresses to cirrhosis. However, the mechanisms underlying iron-induced fibrosis remain unclear. Transformation of fat-storing cells to collagen-producing myofibroblasts has been proposed to be induced either by iron; by lipid peroxides or other cellular factors released from iron-loaded, damaged hepatocytes; or by profibrogenic factors produced by activated Kupffer cells. In addition, iron may enhance the cytotoxic and, possibly, fibrogenic effects of other liver cell-damaging agents, such as alcohol or hepatotrophic viruses. Once cirrhosis is manifest, patients with GH demonstrate a 200-fold increase in the risk for development of hepatocellular carcinoma. In vitro, iron has been shown to possess mutagenic properties, but the results from in vivo models in which the genotoxic effects of iron overload have been studied are variable. Similarly, although iron has mitostimulatory effects on hepatocytes in vivo and preneoplastic cells in vitro, its role in tumor promotion and/or progression still remains unclear. Cirrhosis itself is of central importance in the carcinogenic process, but whether or not iron acts as an additional risk factor in this process, alone or by enhancing the tumorigenic properties of other hepatocarcinogens, has yet to be established.

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The mobilization of ferritin iron by liver cytosol. A comparison of xanthine and NADH as reducing substrates

Cited by 48 publications

References 28 publications

Combination of Iron Overload Plus Ethanol and Ischemia Alone Give Rise to the Same Endogenous Free Iron Pool

Combination of Iron Overload Plus Ethanol and Ischemia Alone Give Rise to the Same Endogenous Free Iron Pool

Roles of ATP and NADPH in Formation of the Fe-S Cluster of Spinach Ferredoxin

Iron as a Hepatotoxin

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