John L. Beard1
A recent article by Salonen and colleagues in Circulation has sparked the interest of a number of individuals both within and outside of the scientific community (Salonen et al., 1992). The research question posed by the authors and suggested by a growing number of observations was relatively straightforward: Is excess body iron, as indicated by the plasma ferritin concentration, a significant positive risk factor for myocardial infarction? The biologic feasibility of this question has its roots in the reasonably well established in vitro relationships between free-radical production and iron content in physiologic solutions (Halliwell and Gutteridge, 1990; Reif, 1992). The Haber-Weiss reaction (equation 1)
can be modified in the presence of Fe+3 to a much faster set of reactions (equations 2 and 3) called the Fenton reaction:
The hypotheses concerning the effect of the chronic toxicity of iron with regard to its relationship with cancer, atherosclerosis, and neurodegenerative disorders have a common theme in the iron-catalyzed production of highly reactive oxygen species. A recent census lists 60 human diseases in which oxidant stress is thought to play a role (Halliwell, 1987).
Although it is true that iron can catalyze a number of biologically undesirable reactions in vitro, iron is nearly always chelated to low-molecular-weight compounds or is associated with macromolecules such as proteins, lipids, carbohydrates, and nucleic acids in vivo and under nonpathologic conditions. Free
iron can be liberated by redox reagents from iron-protein complexes but is frequently oxidized to the ferric state by ceruloplasmin (Gutteridge, 1986; Gutteridge et al., 1980). Recent evidence obtained by electromagnetic proton resonance suggests that the Fenton reaction occurs only when plasma is exposed to atmospheric oxygen and that even iron-overloaded plasma does not produce the superoxide-driven Fenton reaction (Minetti et al., 1992). Some authors have suggested that an endogenous pool of low-molecular-weight proteins such as di- and trinucleotides, citrate, acetate, and urate complexed to ferrous iron are sources of hydroxyl radicals (Floyd, 1983).
The highly reactive product oxidant molecules are the sources of extensive oxidative stress to cellular systems and are the basis of extensive studies by Halliwell and Gutteridge (1990). The sources of this ''free iron'' in vivo are unknown at this time, and the in vivo locations are undetermined. Oxidized iron is transported in a tightly bound fashion to transferrin in the plasma pool and is not readily removed by most endogenous or exogenous chelators of iron unless the pH drops significantly below 6.0. Thus, the amount of free iron in plasma in normal physiologic states is extremely low and is an unlikely source of iron for the Fenton reaction. A second possible source of iron in the plasma pool or in cells is ferritin (Reif, 1992). Apoferritin is composed of 24 protein sub units containing either heavy or light chains. The heavy-chain sub unit has considerable ferroxidase activity, whereas the amounts of both chains regulate the rate of entry and exodus of ferric iron from its ferric oxide core (Cozzi et al., 1990; Craelius et al., 1974). Ferritin is usually less than 20 percent saturated with iron while in the plasma compartment. The iron in fully loaded ferritin is more labile than that in normally loaded ferritin (Gutteridge et al., 1983). In vitro studies have frequently driven the mobilization of this ferritin-bound iron by adding supraphysiologic amounts of oxidants, chelators, and iron-loaded ferritin. A number of compounds with a reducing potential in excess of -230 mV can remove ferritin-bound iron at physiologic pH. Unfortunately, most in vitro studies have used chelators and oxidizing agents that have iron-binding affinities in excess of those likely to exist for in vivo chelators (Reif, 1992). The presence of appropriate antioxidants can prevent this iron removal. Thomas and colleagues (1985) and others (Gutteridge et al., 1983) have shown increased lipid peroxidation when iron is released from ferritin. The extent of damage can be limited by the addition of iron chelators such as desferoxamine, although its binding affinity for iron (1031) is much higher than those of other likely in vivo chelators.
The redox potential for superoxide (0.33 mV) suggests that superoxide is capable of reducing the ferric iron core of ferritin (Crighton et al., 1980). This superoxide is generated in vivo by xanthine oxidase during respiratory bursts by neutrophils and during reperfusion injury of ischemic tissues (Bolann and Ulvik, 1990). Although superoxide is able to mobilize few ferrous iron atoms in normally saturated ferritin, the number increases 3.5-fold by the addition of the chelator EDTA. Other studies show that the iron liberated from ferritin by superoxide can be scavenged by both transferrin and lactoferrin or reoxidized by
ceruloplasmin in vitro (Monteiro and Winterbourn, 1988; Samokyszyn et al., 1989, 1991). Transferrin and lactoferrin are unlikely donators given their high binding affinity for iron (1024) at physiologic pH. In contrast, transferrin and lactoferrin inhibit iron-catalyzed lipid peroxidation in vitro (Gutteridge et al., 1981). Heme iron can be removed by oxidants such as H2O2 in vitro (Puppo and Halliwell, 1988). This can cause cytotoxicity in cells exposed to both heme and oxidant stress. Hemopexin and haptoglobin complexes with hemoglobin both act to prevent lipid peroxidation (Gutteridge, 1987).
The direct evidence for free iron availability comes from the bleomycin-re-active iron assay or inhibition of reactions by the iron chelator desferoxamine. Bleomycin-detectable iron is absent from the plasma, serum, and synovial fluid of healthy adult individuals. It can be found in the plasma of premature and full-term neonates, with higher levels occurring in the premature neonate group (Evans et al., 1992). These levels correspond to the ability of surfactant from neonates to induce lipid peroxidation (Moison et al., 1993). Bleomycin-detectable iron is also found in the plasma and synovial fluid of patients with idiopathic hemochromatosis, bone marrow transplant recipients, and patients with acute nonlymphocytic leukemia (Foerder et al., 1992; Gordeuk and Brittenham, 1992; Gutteridge, 1992; Pillay and Makgoba, 1992). This free iron has also been found in the gruel of atherosclerotic lesions (Smith et al., 1992).
The oxidation of low-density lipoproteins (LDLs) has been experimentally related to the presence of iron (Kuzuya et al., 1990; Steinberg et al., 1989). An increased proportion of LDLs was oxidized after exposure to high levels of iron, and there was a more rapid uptake of LDLs into cells. It is the rapid and relatively uncontrolled uptake of these oxidized LDLs that are key elements in the current hypothesis of the pathogenesis of coronary heart disease (CHD) (Steinberg et al., 1989).
The study by Salonen and colleagues (1992) that has caused such recent public concern was a prospective examination of novel risk factors for acute myocardial infarction and atherogenesis (AMI). The subject population was a group of 3,235 eastern Finnish men who were enrolled in the study at ages 42, 48, 54, and 60 years and who were followed for 5 years. The authors established by a proportional hazards model that an elevated plasma ferritin concentration was one of the significant factors for AMI after a statistical adjustment for age and year of enrollment. The relative risk was 2.2 for men with a serum ferritin concentration of 200 µg/liter or greater. Further separation of the elevated ferritin group into groups with serum ferritin concentrations of 200-400 and greater than 400 µg/liter did not change the risk ratio, indicating an effect well within a range of ferritin concentrations at the high end of normal. The men who had heart attacks had a higher mean ferritin concentration (231 ± 215 µg/liter) than those who did not (165 ± 146 µg/liter). It is important to note that
equal numbers of men with serum ferritin concentrations of less than 200 µg/liter and greater than 200 mg/liter had heart attacks. The authors noted that a significant difference persists between these two groups after a covariance adjustment is made on the basis of other risk factors such as lipoprotein concentrations and smoking history. The distribution of serum ferritin concentrations showed that about 10 percent of the men in their fourth and fifth decades of life had a serum ferritin concentration of greater than 280 µg/liter. This percentage is comparable to that reported by Salonen and colleagues (1992) for the non-AMI portion of the sample and is a considerably lower percentage than that in the AMI sample (18 percent). Thus, although the non-AMI sample had a distribution similar to that in the U.S. population, the AMI group appeared to be shifted to the right of the mean and to have a small group of subjects with extremely high serum ferritin concentrations. A recent estimate of the prevalence of the hemochromatosis gene defect in Europe and the United States is that 4.5 people per 1,000 population are homozygous, and about 12.5 percent of the population is estimated to be heterozygous. Although the gene prevalence in the sample population is not known, it is possible that this iron-loading gene defect plays a significant role in the established statistical relationship. Previous reports demonstrate a low prevalence of less than 1/1,000 population in other parts of Finland, but also recognize that pockets of increased prevalence may exist in the Finnish population (Karlsson et al., 1988). Near the upper end of the ferritin distribution, the transferrin saturation can approach 100 percent (Bothwell and Charlton, 1982). It is at this point that free iron may be present in plasma and act in the aforementioned manner as a participant in the Haber-Weiss reaction (Aruoma et al., 1988). Congestive heart failure is characteristic of hereditary hemochromatosis and is prevented by chelation or phlebotomy. Recent evidence in the reperfusion-ischemia literature demonstrates a strong role for chelatable iron in the initiation of cellular oxidative damage (Van der Kraaij et al., 1988; Williams et al., 1991).
The positive effects of ferritin on oxidation-mediated damage, however, should be considered. Apoferritin added to cultured endothelial cells protects them from oxidant-mediated cytolysis because of its strong ferroxidase affinity (Balla et al., 1991). The antioxidant status of the microenvironment in vivo may ultimately determine whether iron-catalyzed oxidative damage to LDLs is a significant component of atherogenesis. In a prospective study of U.S. physicians, an increased risk (relative risk of 1.1) was reported for those with a high level of serum ferritin, although dietary iron had no relationship to risk of CHD (Rimm et al., 1993). This does not support the hypothesis that dietary iron increases coronary risk in men, nor is it consistent with a 5 percent increase in the risk of CHD with a l-mg increase in iron intake per day, as suggested by Salonen and colleagues (1992).
The experimental evidence relating iron status to carcinogenesis is usually derived from studies that use very large quantities of iron. For example, mammary carcinogenesis induced by 1-methyl-nitrosourea is increased in rots fed 1,200 mg/ml of iron compared with that in rats fed 20 or 2 mg/ml (Thompson et al., 1991). In a model of induced mammary carcinogenesis, mice fed 5 mg/kg of iron developed tumors at a faster rate than mice fed iron at 180 mg/kg. There was no increase in overall tumor incidence. Iron potentiates 1,2-dimethyhydrazine-induced colon cancer (20 mg/kg) at a level of 3.5 percent ferrous fumarate (11,504 mg/kg of elemental iron) in the diet (Siegers et al., 1988, 1992). Experimental iron deficiency is associated with delayed onset time of experimental liver tumors (Vitale et al., 1977), whereas choline-deficient rats fed a low-iron diet developed fewer preneoplastic liver lesions than rats fed 330 mg/kg of iron (Yoshigi et al., 1992).
In a screening designed to assess the carcinogenicity of pharmaceutical preparations, an increased risk of lung cancer was noted among male users of nonprenatal iron formulations (Friedman and Ury, 1980, 1983). A 24-hour recall survey of the Transkei region of South Africa found a significant increase in intake of dietary iron among those at increased risk of esophageal cancer (Groenwald et al., 1981). In a retrospective case-control study of 186 subjects, iron consumption varied inversely with the size of colonic polyps but showed no correlation with the size of the initial dysplasia (Hoff et al., 1986). A prospective study of colorectal cancer in Majorca concluded that the daily iron intake was greater in females who developed colon cancer than in population controls (Benito, 1991). Data from the first National Health and Nutrition Examination Survey indicate that the total iron-binding capacity is lower and the transferrin saturation is higher among men who developed cancer (Stevens et al., 1988). An association in women was evident only at extremely high transferrin saturations. Similar and opposite relationships affected by gender are evident in other studies (Selby and Friedman, 1988; Stevens et al., 1986). It is not dear whether these data clarify any role in the pathogenesis of iron-related carcinogenesis.
Brain Iron and Disease
A number of neurologic disorders, including Parkinson's disease (Olanow et al., 1992), multiple sclerosis (Drayer et al., 1987), Alzheimer's disease (Connor, 1992), and Hallervorden-Spatz disease (Swaiman, 1991), are associated with disruptions in iron homeostasis in the brain. It is clear that normal neurologic function is dependent on normal iron homeostasis. The brain has the highest rate of oxidative metabolism of any organ in the body, which probably accounts for the finding that levels of iron are higher in the brain that in any organ except the liver (Hallgren and Sourander, 1958).
Research attention has focused on the involvement of iron in neurologic disease, particularly as it relates to oxidative damage. Data describing the postmortem brain iron contents of individuals who had Parkinson's disease (Sofic et al., 1988) showed a 176 percent increase in total iron and a 255 percent increase in ferric iron in the substantial nigra; no changes were observed in the cortex, hippocampus, putamen, or globus pallidus.
Iron dysfunction has long been suspected in Alzheimer's disease. Iron is a significant component of senile plaques, and iron encrustation of blood vessels in the brains of patients with Alzheimer's disease is a common observation (Connor, 1992). Iron levels in the hippocampus, amygdala, nucleus basalis of Meynert (Thompson et al., 1988), and the cerebral cortex (Connor et al., 1992) are elevated in patients with Alzheimer's disease. Analyses of iron transport and storage proteins suggest that iron mobility is decreased in the brains of patients with Alzheimer's disease compared with that in the brains of normal subjects (reviewed in Connor, 1992). Decreased iron mobility would likely be associated with decreased metabolic activity and increased peroxidative damage—bothwell-established phenomena in the brains of patients with Alzheimer's disease, with no known muse. Recently, an iron-responsive element has been reported on the messenger RNA for the amyloid precursor protein (Tanzi and Hyman, 1991; Zubenko et al., 1992), suggesting that iron is somehow involved in regulating amyloid precursor protein synthesis.
Perhaps equally as important as its function in normal activity is the role of iron in oxidative injury leading to membrane damage and, ultimately, cell death (Halliwell, 1991; Zaleska and Floyd, 1985). A decrease in cell membrane fluidity within the central nervous system is considered part of the pathogenesis of aging, and an increase in flee-radical production has been demonstrated in the brain tissues of patients with Alzheimer's disease (reviewed in Halliwell, 1991). Iron is a critical factor in the induction of events leading to lipid peroxidative damage in the brain (Zaleska and Floyd, 1985). The relationship between iron and oxidant stress has led to the hypothesis that in patients with Parkinson's disease, iron may contribute to neuronal cell death and tissue damage, especially in the substantial nigra but also in the caudate putamen (Olanow et al., 1992). Thus, the dual nature of iron dictates that it must be both available to cells and stringently regulated. Imbalance of iron or its regulatory proteins in the brain could result in substantial damage to neurons and glia, leading to neurodegeneration and neurologic dysfunction.
Investigators have found that in comparison with normal aged tissue, the transferrin concentration is consistently lower, ferritin levels are either slightly lower or unchanged, and iron levels are elevated in tissues from individuals
with Alzheimer's disease (Connor et al., 1992). These obligations suggest the decreased mobility of iron and the increased amount of iron stored per mole of ferritin. Such an increase in iron, even if it is stored in ferritin, could increase the likelihood of iron-induced lipid peroxidative damage.
Perhaps most relevant to Alzheimer's disease and iron metabolism are reports of abnormalities in oxidative metabolism in patients with Alzheimer's disease (Gibson and Peterson, 1981). A correlation between the cellular and regional distributions of transferrin receptors and the levels of cytochrome oxidase activity in the brain underscores the importance of iron and oxidative activity (Morris et al., 1992a, b). A recent report has shown a loss of transferrin receptors in specific regions of the brain in patients with Alzheimer's disease, including the hippocampus—an area where mitochondrial enzymes and metabolic activity are decreased in patients with Alzheimer's disease (Gibson and Peterson, 1981; Kalaria et al., 1992). In addition, cholinergic neurotransmission, a well-known defect in patients with Alzheimer's disease, is highly susceptible to impaired oxidative metabolism (Blass and Gibson, 1991; Gibson and Peterson, 1981). This latter observation is particularly exciting in relation to a report that transferrin receptor density is relatively high in the nucleus basalis of Meynert (Morris et al., 1989). The demonstration that iron is also involved in the synthesis and degradation of fatty acids and cholesterol in the brain may have direct relevance to a recent report that cholesterol concentrations are lower in brain regions known to undergo the neurodegenerative changes mused by Alzheimer's disease (Mason et al., 1991).
Recently developed free-radical scavengers and specific iron chelators that cross the blood-brain barrier have already been used as palliative agents in central nervous system trauma. Determination of the effectiveness of these agents in treating Alzheimer's disease would augment existing data. An iron chelator (Desferal) has already been used in a study to abate cognitive decline in patients with Alzheimer's disease (McLachlan et al., 1991). Although the study was controversial in design and interpretation (among other concerns, the study was interpreted to suggest that the effect was due to aluminum without considering the effect of iron), the investigative approach involving iron or aluminum and iron chelation is worthy of pursuit.
Iron-regulatory proteins may also be involved in the development of Alzheimer's disease. Under physiologic conditions, aluminum, which has been implicated in the pathogenesis of Alzheimer's disease, can be bound to transferrin and transported (Aschner and Aschner, 1990; Roskams and Connor, 1990). Roskams and Connor (1990) have shown that a transferrin-aluminum complex can bind to the transferrin receptor in the brain with nearly the same affinity as a transferrin-iron complex. These data suggest that aluminum gains access to the brain by utilizing the extant system for iron transport. Aluminum may also bind to ferritin in patients with Alzheimer's disease, diminishing the ability of ferritin to bind and release iron, further leading to oxidative damage (Dedman et al., 1992; Fleming and Joshi, 1987).
The key components necessary to regulate iron delivery, storage, and utilization are found in the highest levels within one cell type in the brain: the oligodendrocyte. Oligodendrocytes are responsible for the production and maintenance of myelin, processes that are disrupted in patients with multiple sclerosis (MS), the prototype of demyelinating diseases. The cellular patterns for iron and transferrin are both altered around MS plaques. Iron is found within MS plaques, and transferrin which normally should be located in oligodendrocytes, is found instead in astrocytes surrounding MS plaques and in demyelinating areas in central pontine myelinolysis (Craelius et al., 1982; Esiri et al., 1976; Gocht and Lohler, 1990). Recent magnetic resonance imaging data showing iron accumulation in specific brain regions of patients with MS indicate a general disruption in iron regulation (Esiri et al., 1976). Other demyelinating diseases, such as Pelizaeus-Merzbacher disease (reduced transferrin levels and appearance of biochemically abnormal transferrin), progressive rubella panencephalitis (iron deposits in cells in centrum ovale), and the demyelination associated with human immunodeficiency virus infection (siderotic microglia in the demyelinated regions) all strongly indicate that iron homeostasis is disrupted at the cellular level in patients with dysmyelinating disorders (Gelman et al., 1992; Jaeken et al., 1984; Koeppen et al., 1988; Valk, 1989).
The physiology of oligodendrocytes, including the mechanism for myelin production and maintenance, is poorly understood. Although the cause and effect (demyelination) of MS are unknown, induction of oxidative damage by iron has been implicated. In relation to dysmyelinating diseases, the iron-rich, lipidrich myelin tracts could be a prime target for oxidative damage. Indeed, in an animal model of autoimmune demyelination, the clinical and pathologic symptoms associated with experimental autoimmune neuritis can be reduced in the presence of endogenously administered antioxidants (Hartung et al., 1988).
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