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P Ponka

Publications and source records attributed to P Ponka.

At least 37 records · Page 2Linked to original sources
PubMed1999

The transferrin receptor: role in health and disease.

The transferrin receptor is a membrane glycoprotein whose only clearly defined function is to mediate cellular uptake of iron from a plasma glycoprotein, transferrin. Iron uptake from transferrin involves the binding of transferrin to the transferrin receptor, internalization of transferrin within an endocytic vesicle by receptor-mediated endocytosis and the release of iron from the protein by a decrease in endosomal pH. With the exception of highly differentiated cells, transferrin receptors are probably expressed on all cells but their levels vary greatly. Transferrin receptors are highly expressed on immature erythroid cells, placental tissue, and rapidly dividing cells, both normal and malignant. In proliferating nonerythroid cells the expression of transferrin receptors is negatively regulated post-transcriptionally by intracellular iron through iron responsive elements (IREs) in the 3' untranslated region of transferrin receptor mRNA. IREs are recognized by specific cytoplasmic proteins (IRPs; iron regulatory proteins) that, in the absence of iron in the labile pool, bind to the IREs of transferrin receptor mRNA, preventing its degradation. On the other hand, the expansion of the labile iron pool leads to a rapid degradation of transferrin receptor mRNA that is not protected since IRPs are not bound to it. However, some cells and tissues with specific requirements for iron probably evolved mechanisms that can override the IRE/IRP-dependent control of transferrin receptor expression. Erythroid cells, which are the most avid consumers of iron in the organism, use a transcriptional mechanism to maintain very high transferrin receptor levels. Transcriptional regulation is also involved in the receptor expression during T and B lymphocyte activation. Macrophages are another example of a cell type that shows 'unorthodox' responses in terms of IRE/IRP paradigm since in these cells elevated iron levels increase (rather than decrease) transferrin receptor mRNA and protein levels. Erythroid cells contain the highest mass of the total organismal transferrin receptors which are released from reticulocytes during their maturation to erythrocytes. Hence, plasma contains small amounts of transferrin receptors which represent a soluble fragment of the extracellular receptor domain. Measurements of serum transferrin receptor concentrations are clinically useful since their levels correlate with the total mass of immature erythroid cells.

Animals↗
PubMed1999

Cellular iron metabolism.

Iron is essential for oxidation-reduction catalysis and bioenergetics, but unless appropriately shielded, iron plays a key role in the formation of toxic oxygen radicals that can attack all biological molecules. Hence, specialized molecules for the acquisition, transport (transferrin), and storage (ferritin) of iron in a soluble nontoxic form have evolved. Delivery of iron to most cells, probably including those of the kidney, occurs following the binding of transferrin to transferrin receptors on the cell membrane. The transferrin-receptor complexes are then internalized by endocytosis, and iron is released from transferrin by a process involving endosomal acidification. Cellular iron storage and uptake are coordinately regulated post-transcriptionally by cytoplasmic factors, iron-regulatory proteins 1 and 2 (IRP-1 and IRP-2). Under conditions of limited iron supply, IRP binding to iron-responsive elements (present in 5' untranslated region of ferritin mRNA and 3' untranslated region of transferrin receptor mRNA) blocks ferritin mRNA translation and stabilizes transferrin receptor mRNA. The opposite scenario develops when iron in the transit pool is plentiful. Moreover, IRP activities/levels can be affected by various forms of "oxidative stress" and nitric oxide. The kidney also requires iron for metabolic processes, and it is likely that iron deficiency or excess can cause disturbed function of kidney cells. Transferrin receptors are not evenly distributed throughout the kidney, and there is a cortical-to-medullary gradient in heme biosynthesis, with greatest activity in the cortex and least in the medulla. This suggests that there are unique iron/heme metabolism features in some kidney cells, but the specific aspects of iron and heme metabolism in the kidney are yet to be explained.

Animals↗
PubMed1999

Cell biology of heme.

Heme is a complex of iron with protoporphyrin IX that is essential for the function of all aerobic cells. Heme serves as the prosthetic group of numerous hemoproteins (eg, hemoglobin, myoglobin, cytochromes, guanylate cyclase, and nitric oxide synthase) and plays an important role in controlling protein synthesis and cell differentiation. Cellular heme levels are tightly controlled; this is achieved by a fine balance between heme biosynthesis and catabolism by the enzyme heme oxygenase. On a per-cell basis, the rate of heme synthesis in the developing erythroid cells is at least 1 order of magnitude higher than in the liver, which is in turn the second most active heme producer in the organism. Differences in iron metabolism and in genes for 5-aminolevulinic acid synthase (ALA-S, the first enzyme in heme biosynthesis) are responsible for the differences in regulation and rates of heme synthesis in erythroid and nonerythroid cells. There are 2 different genes for ALA-S, one of which is expressed ubiquitously (ALA-S1), whereas the expression of the other (ALA-S2) is specific to erythroid cells. Because the 5'-untranslated region of the erythroid-specific ALA-S2 mRNA contains the iron-responsive element, a cis-acting sequence responsible for translational induction of erythroid ALA-S2 by iron, the availability of iron controls protoporphyrin IX levels in hemoglobin-synthesizing cells. In nonerythroid cells, the rate-limiting step of heme production is catalyzed by ALA-S1, whose synthesis is feedback-inhibited by heme. On the other hand, in erythroid cells, heme does not inhibit either the activity or the synthesis of ALA-S but does inhibit cellular iron acquisition from transferrin without affecting its utilization for heme synthesis. This negative feedback is likely to explain the mechanism by which the availability of transferrin iron limits heme synthesis rate. Moreover, in erythroid cells heme seems to enhance globin gene transcription, is essential for globin translation, and supplies the prosthetic group for hemoglobin assembly. Heme may also be involved in the expression of other erythroid-specific proteins. Furthermore, heme seems to play a role in regulating either transcription, translation, processing, assembly, or stability of hemoproteins in nonerythroid cells. Heme oxygenase, which catalyzes heme degradation, seems to be an important enzymatic antioxidant system, probably by providing biliverdin, which is an antioxidant agent.

5-Aminolevulinate Synthetase↗
PubMed1998

The iron chelator pyridoxal isonicotinoyl hydrazone (PIH) protects plasmid pUC-18 DNA against *OH-mediated strand breaks.

Pyridoxal isonicotinoyl hydrazone (PIH) has previously been studied for use in iron chelation therapy in iron-overload diseases. It is an efficient in vitro antioxidant due to its Fe(III) complexing activity (Schulman, H. M., et al. Redox Report 1:373-378; 1995). Pathologies associated with iron-overload include hepatic and other cancers. Since oxidative alterations of DNA can be linked to the development of cancer, we decided to study whether PIH protects DNA against in vitro oxidative stress. We report here that pUC-18 plasmid DNA is damaged by *OH radicals generated from Fe(II) plus H2O2 or from Fe(II) plus hypoxanthine/xanthine oxidase. The DNA damage was quantified by determining the diminution of supercoiled DNA forms after oxidative attack using agar gel electrophoresis. Micromolar amounts of PIH (20-30 microM) were able to half-protect DNA from iron (1-7.5 microM)-mediated *OH formation. The antioxidant capacity of PIH was significantly higher than that of some of its analogs and desferrioxamine. PIH and some of its analogues could also inhibit the oxidative degradation of 2-deoxyribose caused by Fenton reagents. Since we observed that PIH enhances the Fe(II) autoxidation rate, measured by the ferrozine technique, PIH may limit *OH formation and consequently DNA damage by decreasing the amount of Fe(II) available to catalyze Fenton reactions.

Antioxidants↗
PubMed1998

Development of iron chelators to treat iron overload disease and their use as experimental tools to probe intracellular iron metabolism.

The development of an orally effective iron (Fe) chelator for the treatment of Fe overload diseases such as beta-thalassemia has been a difficult challenge. Even though the drug in current clinical use, desferrioxamine (DFO), is efficient and remarkably free of toxicity, it suffers from not being orally effective and requiring long subcutaneous infusion to mobilize sufficient quantities of Fe. In addition, DFO is very expensive, which precludes it from treating most of the world's thalassemic population. Therefore, the development of an economical and orally effective Fe chelator is of great importance. Despite the screening of a wide range of structurally diverse ligands from both natural and synthetic sources, few compounds have been promising enough to proceed to clinical trials. In the current review, the properties of an ideal chelator are discussed, followed by a description of the most successful ligands that have been identified. Apart from the use of Fe chelators as therapeutic agents, some of these compounds have also been useful as experimental probes to investigate cellular Fe metabolism. We describe here the most important of these studies.

Deferoxamine↗
PubMed1998

Pyridoxal isonicotinoyl hydrazone and its analogs: potential orally effective iron-chelating agents for the treatment of iron overload disease.

At present, the only iron (Fe) chelator in clinical use for the treatment of Fe overload disease is the tris-hydroxamate deferoxamine (DFO). However, DFO suffers from a number of disadvantages, including the need for subcutaneous infusion (12 to 24 hours a day, 5 or 6 times per week), its poor intestinal absorption, and high cost. Therefore, there is an urgent need for an efficient, economical, and orally effective Fe chelator. Pyridoxal isonicotinoyl hydrazone (PIH) is a tridentate Fe-chelating agent that shows high Fe chelation efficacy both in vitro in cell culture models and also in vivo in rats and mice. In addition, this chelator is relatively nontoxic, economical to synthesize, and orally effective, and it shows high selectivity and affinity for Fe. However, over the last 10 years the development of PIH and its analogs has largely been ignored because of justifiable interest in other ligands such as 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Unfortunately, recent clinical trials have shown that significant complications occur with L1 therapy, and it is controversial whether this chelator is effective at reducing hepatic Fe levels in patients. Because of the current lack of a clinically useful Fe chelator to replace DFO, PIH and its analogs appear to be potential candidate compounds that warrant further investigation. In this review we will discuss the studies that have been performed to characterize these chelators at the chemical and biologic levels as effective agents for treating Fe overload. The evidence from the literature suggests that these ligands deserve further careful investigation as potential orally effective Fe chelators.

Animals↗
PubMed1998

Ureter obliteration transiently depresses erythropoietin production.

BACKGROUND: The erythropoietin (EPO) gene is activated in peritubular cells of the renal cortex in response to hypoxia and EPO is secreted into the circulation. Oxygen tension in the venous blood normally determine EPO elaboration, and, therefore, oxygen consumption in the kidney appears to be an essential part of the oxygen-sensing physiological mechanism. As renal oxygen consumption is closely linked to urine production, we have compared responsiveness of the EPO gene to diminished oxygen supply in the normal kidney with that of the hydronephrotic kidney, resulting from ureter ligation. METHODS: Erythropoietin mRNA was determined in RNA extracted from murine kidneys at various times up to 61 days after ureter ligation. Mice were exposed to hypoxia for 4 h before being killed. RESULTS: Unilateral ureter ligation significantly decreased EPO mRNA levels in the affected kidney. However, the ability to increase EPO mRNA recovered between days 4 and 22, despite persisting ureter ligation. CONCLUSION: Our results demonstrate a dissociation between the excretory functions of the kidney and EPO production. Moreover, they show an early but transient suppression of EPO gene responsiveness to hypoxia after ureter ligation.

Animals↗
PubMed1998

Function and regulation of transferrin and ferritin.

Iron represents a paradox for living systems by being essential for a wide variety of metabolic processes (oxygen transport, electron transport, DNA synthesis, etc) but also having the potential to cause deleterious effects. Because of Iron's virtual insolubility and potential toxicity under physiological conditions, specialized molecules for the acquisition, transport, and storage of iron in a soluble, nontoxic form have evolved to meet cellular and organismal iron requirements. Physiologically, the majority of cells in the organism acquire iron from a well-characterized plasma glycoprotein, transferrin. Iron uptake from transferrin is reasonably well understood, and involves the binding of transferrin to the transferrin receptor, internalization of transferrin within an endocytic vesicle by receptor-mediated endocytosis, and the release of iron from the protein by a decrease in endosomal pH. Most of the transferrin-bound iron is used for the synthesis of hemoglobin by developing erythroid cells. Senescent erythrocytes are internalized by the macrophages that liberate hemoglobin iron and release it back to plasma transferrin at a rate that normally matches the rate of iron transport for erythropoiesis. Unfortunately, the mechanisms and controls involved in the release of iron from macrophages have not been defined. After iron release from transferrin within endosomes, iron passes through the endosomal membrane by ill-understood mechanisms and then enters the poorly characterized intracellular labile pool. Iron in the labile pool that exceeds requirement for the synthesis of functional heme and nonheme iron-containing proteins is stored within the iron-storage protein, ferritin. Evidence in vitro indicates that relatively soluble ferrous iron can enter or be released from ferritin. However, we know virtually nothing about the exchange of iron with ferritin in intact cells, and some evidence indicates that the degradation of the ferritin protein may be an important mechanism for the release of iron within the cell. Cellular iron uptake and storage are coordinately regulated through a feedback control mechanism mediated at the post-transcriptional level by cytoplasmic factors know as iron-regulatory proteins 1 and 2. These proteins "sense" levels of iron in the transit pool and, when iron in this pool is scarce, they bind to stem-loop structures known as iron-responsive elements on the 5' untranslated region of the ferritin mRNA and 3' untranslated region of the transferrin mRNA. Such a binding inhibits translation of ferritin mRNA and stabilizes the mRNA for transferrin receptors. The opposite scenario develops when iron in the transit pool is plentiful. This remarkable regulatory mechanism prevents the expansion of a catalytically active intracellular iron pool, while maintaining sufficient concentrations of the metal for metabolic needs.

Ferritins↗
PubMed1997

Selective inhibition of l kappaB alpha phosphorylation and HIV-1 LTR-directed gene expression by novel antioxidant compounds.

Oxidative stress activates the NF-kappaB/Rel transcription factors which are involved in the activation of numerous immunoregulatory genes and the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). In the present study, we examined the effects of established and novel compounds including antioxidants, ribonucleotide reductase inhibitors, and iron chelators on NF-kappaB activation and HIV LTR-mediated gene expression induced by TNF-alpha. N-Acetylcysteine (NAC), pyrrolidinedithiocarbamate (PDTC), and Trimidox (TD) at various concentrations inhibited TNF-alpha-induced NF-kappaB binding in Jurkat cells. Pretreatment of cells with these compounds prior to stimulation prevented I kappaB alpha degradation. Phosphorylation of I kappaB alpha, a prerequisite for its signal-induced degradation, was abrogated in these cells, indicating that oxidative stress is an essential step in the NF-kappaB activation pathway. On the other hand, iron chelators desferrioxamine, pyridoxal isonicotinoyl hydrazone (PIH), and salicylaldehyde isonicotinoyl hydrazone (SIH) showed no inhibition of TNF-alpha-induced NF-kappaB DNA-binding activity. Synergistic induction of HIV-1 LTR-mediated gene expression by TNF-alpha and the HIV-1 transactivator Tat in Jurkat cells was significantly suppressed in the presence of NAC and TD, but not PDTC. The inhibition of NAC and TD on LTR-directed gene expression was diminished when NF-kappaB-binding sites in the LTR were deleted, indicating that these compounds affected the NF-kappaB component of the synergism. Iron chelators PIH and SIH also showed some inhibitory effect on LTR-mediated gene activation, presumably through an NF-kappaB-independent mechanism. These experiments demonstrate that TD, at concentration 50 times lower than the effective concentration of NAC, potently inhibits NF-kappaB activity and suppresses HIV LTR expression.

Antioxidants↗
PubMed1997

The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells.

Iron uptake by mammalian cells is mediated by the binding of serum Tf to the TfR. Transferrin is then internalized within an endocytotic vesicle by receptor-mediated endocytosis and the Fe released from the protein by a decrease in endosomal pH. Apart from this process, several cell types also have other efficient mechanisms of Fe uptake from Tf that includes a process consistent with non-specific adsorptive pinocytosis and a mechanism that is stimulated by small-Mr Fe complexes. This latter mechanism appears to be initiated by hydroxyl radicals generated by the Fe complexes, and may play a role in Fe overload disease where a significant amount of serum non-Tf-bound Fe exists. Apart from Tf-bound Fe uptake, mammalian cells also possess a number of mechanisms that can transport Fe from small-Mr Fe complexes into the cell. In fact, recent studies have demonstrated that the membrane-bound Tf homologue, MTf, can bind and internalize Fe from 59Fe-citrate. However, the significance of this Fe uptake process and its pathophysiological relevance remain uncertain. Iron derived from Tf or small-Mr complexes is probably transported into mammalian cells in the Fe(II) state. Once Fe passes through the membrane, it then becomes part of the poorly characterized intracellular labile Fe pool. Iron in the labile Fe pool that is not used for immediate requirements is stored within the Fe-storage protein, ferritin. Cellular Fe uptake and storage are coordinately regulated through a feedback control mechanism mediated at the post-transcriptional level by cytoplasmic factors known as IRP1 and IRP2. These proteins bind to stem-loop structures known as IREs on the 3 UTR of the TfR mRNA and 5 UTR of ferritin and erythroid delta-aminolevulinic acid synthase mRNAs. Interestingly, recent work has suggested that the short-lived messenger molecule, NO (or its by-product, peroxynitrite), can affect cellular Fe metabolism via its interaction with IRP1. Moreover, NO can decrease Fe uptake from Tf by a mechanism separate to its effects on IRP1, and NO may also be responsible for activated macrophage-mediated Fe release from target cells. On the other hand, the expression of inducible NOS which produces NO, can be stimulated by Fe chelators and decreased by the addition of Fe salts, suggesting that Fe is involved in the control of NOS expression.

Antigens, Neoplasm↗
PubMed1997

Prevention of postasphyxia electroretinal dysfunction with a pyridoxal hydrazone.

The newborn retina is particularly sensitive and frequently subjected to peroxidative stresses that result in visual sequelae. We compared two iron chelators, deferoxamine and a newer compound, pyridoxal isonicotinoyl hydrazone (PIH), in protecting the retina of newborn pigs (1-3 d old) from asphyxia-reoxygenation insults. Animals were treated IV with either saline, deferoxamine 15.2 mumol/kg (10 mg/kg) or PIH 34.8 mumol/kg (10 mg/kg); n = 10 in each treatment group. Scotopic and photopic electroretinograms (ERG) were recorded before and 40 min after drug treatment as well as 45 min following a 5-min period of asphyxia by interrupting ventilation. In separate animals the indices of peroxidation, malondialdehyde (MDA: TBARS) and hydroperoxides, were measured in retina at the same times. In saline-treated animals, there was a marked increase in MDA and hydroperoxide concentrations in the retina following the asphyxia-reoxygenation period. This was associated with a decrease in the a- (photoreceptor generated) and b-wave (generated by Müller and bipolar cells) amplitudes measured under photopic (cone-mediated response) and scotopic (rod-mediated response) conditions, and an increase in their implicit times. PIH and deferoxamine prevented the postasphyxial increase in MDA and hydroperoxides. However, only PIH prevented the postasphyxial changes in a- and b-wave amplitudes and implicit times, whereas deferoxamine markedly altered the preasphyxial ERG and provided only partial postasphyxial protection simply to the retinal outer segment. Our findings indicate that the iron chelator PIH effectively inhibits peroxidation and retinal electrophysiological alterations secondary to asphyxia-reoxygenation-induced oxidative stresses to newborn animals, whereas deferoxamine adversely affects retinal function; hence, PIH may be a preferred alternative to deferoxamine.

Animals↗
PubMed1997

The treatment of animal models of malaria with iron chelators by use of a novel polymeric device for slow drug release.

The hydrophilic desferrioxamine (DFO) and the lipophilic salicylaldehyde isonicotinoyl hydrazone (SIH) are iron chelators which inhibit in vitro proliferation of Plasmodium falciparum with similar potency (IC50 approximately 20 microM in 24- to 48-h tests). The in vivo assessment of these drugs was performed on Swiss mice infected with Plasmodium vinckei petteri with novel modes of drug administration and release. The drugs were delivered postpatently either by multiple i.p. injections or by a single i.p. or s.c. insertion of a drug-containing polymeric device which released most of the drug within 7 days at apparently first-order rates. A regimen of three daily i.p injections of 5 mg DFO for 3 consecutive days or a 70-mg dose of the drug given as an i.p. or s.c. polymer implant evoked similar delay and reduction in peak parasitemias and reduced mortality with no apparent signs of toxicity. Relatively faster, but otherwise similar results were obtained with the less hydrophilic SIH. In combination, the two drugs apparently potentiated each other. The polymeric devices were particularly useful for treating Plasmodium berghei K173-infected C57Bl mice, a suggested model of cerebral malaria, in which classical methods of DFO delivery were ineffective. The insertion of a 140-mg DFO-containing device on day 6 postinfection (parasitemia approximately 1%) led to a marked reduction in parasite proliferation, appearance of neurological sequelae and mortality of mice. Our studies indicate that polymeric devices for slow drug release might be highly advantageous for both hydrophilic and lipophilic drugs whose antimalarial efficacy might depend on the maintenance of sustained blood levels. The results obtained with slow-release devices have implications for malaria chemotherapy as well as for iron chelation therapy in iron overload conditions.

Animals↗
PubMed1996

IL-12 p40 messenger RNA expression in target organs during acute graft-versus-host disease. Possible involvement of IFN-gamma.

The onset of acute graft-vs-host disease (aGVHD) is accompanied by macrophage (M phi) priming and the presence of bacteria-derived LPS in the sera of transplanted animals. Priming of M phi occurs during aGVHD despite the suppression of T cell function. We have investigated whether IL-12 mediates the continued production of IFN-gamma during the state of T cell immunosuppression that accompanies aGVHD. Acute GVHD was induced in nonirradiated AxC57BL/6F1 mice by the injection of C57BL/6 lymphoid cells. Despite T cell immunosuppression, M phi became primed, as shown by their expression of inducible nitric oxide synthase mRNA and their production of nitric oxide in response to LPS. Continual exposure to IFN-gamma was required to maintain a primed state in M phi during aGVHD. IL-12 p40 peptide mRNA was increased in M phi purified from animals undergoing aGVHD 14 days after transplantation. Target organs of aGVHD, including thymus, salivary gland, and lung, showed increased IFN-gamma mRNA between days 7 and 14 after transplantation. The increase was accompanied by an induction of mRNA for the p40 peptide of IL-12 and inducible nitric oxide synthase within the target organs. These results provide evidence for localized production of IFN-gamma within aGVHD target organs and suggest that it is mediated by LPS-induced production of IL-12 by M phi. Our data elucidate the mechanism of activation of M phi during aGVHD that results in TNF-alpha and nitric oxide production and delineates the effector role of M phi in the pathology of aGVHD.

Acute Disease↗
PubMed1996

Distribution of iron in reticulocytes after inhibition of heme synthesis with succinylacetone: examination of the intermediates involved in iron metabolism.

Succinylacetone (SA) is an inhibitor of heme synthesis that acts on the enzyme delta-aminolevulinic acid dehydratase. When reticulocytes are incubated with 59Fe-transferrin (59Fe-Tf) in the presence of SA, there is an accumulation of 59Fe in the mitochondrion and in a cytosolic non-heme intermediate that has been described as a putative Fe transporter (Adams et al, Biochim Biophys Acta 1012:243, 1989). Considering these observations, the present study was designed to examine the intermediates of Fe metabolism in control and SA-treated reticulocytes. This investigation showed that in the cytosol of control cells, most 59Fe was incorporated into hemoglobin (Hb) with a minor amount entering ferritin. In addition, a previously unrecognized cytosolic intermediate was identified (band X) that was absent when heme synthesis was inhibited with SA. Upon reincubation of SA-treated reticulocytes with protoporphyrin IX, band X initially increased in intensity and then decreased later in the incubation. In contrast, when 59Fe-labeled control cells were reincubated in the presence of SA and unlabeled diferric Tf, there was a marked decrease in the intensity of band X. These experiments suggest that component X may be an intermediate involved in the transfer of heme in the cytosol. Alternatively, these data could also be interpreted as indicating that band X may be a short-lived hemoprotein. We have confirmed the presence of an 59Fe-containing molecule in the cytosol of SA-treated reticulocytes (band Y) that is not present in control cells. However, when cells were incubated with 59Fe-Tf plus SA and then chased in the presence of SA and unlabeled diferric Tf, there was no decrease in this cytosolic pool of Fe, suggesting that it was not a intermediate supplying Fe for either ferritin or heme synthesis. Finally, there is little low molecular weight (Mr) Fe in reticulocytes, and our studies suggest that the low-Mr Fe present does not behave as an intermediate. Moreover, after inhibition of heme synthesis with SA, 59Fe in the low-Mr compartment was markedly decreased, suggesting that this component may be heme or a low-Mr heme-containing molecule. Considering the apparent lack of a cytosolic Fe transporter in rabbit reticulocytes, an alternative model of intracellular Fe transport is proposed that does not implicate a potentially toxic intermediate pool of low-Mr Fe complexes.

Animals↗
PubMed1996

An update on iron metabolism: summary of the Fifth International Conference on Disorders of Iron Metabolism.

HHC is the most common inherited metabolic disease among the white population worldwide, with a gene frequency of about 10% and a frequency of homozygosity of about 1 of 250. Many patients harbor a common haplotype of informative markers on chromosome 6p2l.23, suggesting a strong founder effect exerted by a common Celtic ancestor. With the advent of screening tests (serum Tf saturation, fe), many subjects with HHC are being identified before development of cirrhosis or diabetes mellitus, and early detection is important because prompt and vigorous iron reduction prevents development of such complications and assures normal life expectancy. The HIC can be estimated as accurately by specialized magnetic resonance imaging or susceptometric measurements as by chemical measurements on liver biopsy specimens. However, biopsy specimens retain value for showing fibrosis/cirrhosis and dysplastic hepatocytes, both of which increase risks of HCC development. There is growing evidence that iron in the liver plays an important role in non-HHC diseases, such as alcoholic liver disease, chronic viral hepatitis, and porphyria cutanea tarda. The complicated, manifold roles of iron in pathogenesis of the latter disorder include enhancement of production and irreversible oxidation of uroporphyrinogen, as well as formation of an inhibitor targeted specifically at hepatic uroporphyrinogen decarboxylase. The nature of the gene and gene product that are abnormal in HHC remain elusive, despite the intense efforts of several investigative groups. The search has been hampered by a dearth of informative markers in HHC patients in the relevant region of chromosome 6p. Note added in proof: The cloning of a candidate gene, the mutation of which may perhaps cause HLA-linked hemochromatosis, has just been reported (Feder et al: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature (Genetics) 1996;399-408). These workers identified a 250-kb region move than three megabases telomeric of the MHC that was identical in 85% of chromosomes of HHC patients. Within this region, they identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations one of which is predicted to inactivate this class of proteins. 83% of 178 patients were homozygous for this mutation (Cys 282Tyr). This variant was also found on 3.2% of control chromosomes, as would be expected for such a common disorder. Functional studies are awaited with great interest.

Congresses as Topic↗