Interaction of iron polymers with blood mononuclear cells and its detection with the Prussian Blue reaction.

An inhibitory effect of iron salts on various immune functions in vitro has been reported in several laboratories during the last few years. This study confirms and extends those observations by showing that iron citrate inhibits the mitogen-induced (PHA, Con A and PWM) lymphocyte proliferation. Such inhibition is observed in the presence of ferric citrate with a metal-to-ligand molar ratio of 1:1 but not with ferric citrate with metal-to-ligand molar ratio 1:20 in which the formation of polynuclear iron complexes is prevented. Increasing the concentration of serum in the culture medium diminished the inhibitory effect of 1:1 ferric citrate. Using the Prussian Blue reaction the presence of ferric iron was observed on the cell surface. It is proposed that the deposition of polynuclear iron complexes on the lymphocytes membrane is one of the possible factors determining the iron inhibitory effect.     

Ferritin and in vivo beryllium toxicity

Beryllium (Be+2), a divalent metal ion, is toxic to both man and animal. Although the molecular basis for its toxicity is unknown, it is well established that micromolar concentrations of beryllium specifically inhibit certain enzymes. Previous in vitro studies have shown that the presence of ferritin, an iron-storage protein, reactivated these enzymes by sequestering beryllium (Price and Joshi, 1984). In the present study we demonstrate in vivo that beryllium and zinc are bound by ferritin in greater amounts than Pb+2, Cu+2, and Cd+2. Beryllium did not induce the synthesis of metallothionein. In animals pretreated with an iron salt (ferric ammonium citrate, 40 mg/kg body wt), liver ferritin was elevated approximately five times and the toxicity of intravenously injected beryllium was significantly attenuated. Excretion and deposition studies suggested that iron salt treatment resulted in a reduction of liver beryllium. Thus the protection against beryllium toxicity by ferric ammonium citrate may be due to increased production of ferritin which binds beryllium and its subsequent elimination in the feces.     

Bioavailability of trivalent iron in oral iron preparations. Therapeutic efficacy and iron absorption from simple ferric compounds and high- or low-molecular weight ferric hydroxide-carbohydrate complexes.

All available results from critical hemoglobin regeneration tests, postabsorption serum iron concentration studies, 59Fe erythrocyte incorporation and 59Fe whole-body retention measurements demonstrate that humans do absorb ferrous iron between 4 and 10 times (in the average about 5 times) better than ferric iron from therapeutic oral 50--250 mg iron doses. Ferrous sulfate iron is 3 to 4 times better available than the iron from ferric ammonium citrate or sulfate. Whereas 100 mg of ferrous sulfate iron/day are sufficient for an optimal oral compensation iron therapy and to produce initial hemoglobin regeneration rates of about 0.26 g/100 ml/day, 400 to 1000 mg of ferric iron/day are necessary for the same therapeutic effect because of the poor bioavailability of ferric iron. The ratio of the dose-absorption relationships for ferric and ferrous 59Fe was shown to decrease from 0.43 for a diagnostic 0.56 mg Fe dose to 0.21 for the therapeutic 50 mg Fe dose in subjects with normal iron stores. Absorption ratios of 0.65 for the 0.56 mg Fe dose and 0.26 for the 50 mg Fe dose were measured in subjects with depleted iron stores. At all dose levels the superior bioavailability of ferrous iron was demonstrable. A high-molecular weight ferric hydroxide-carbohydrate complex (MW similar to 30 000) was palatable but so poorly absorbed that is was practically without effect on hemoglobin regeneration even at a daily 300 mg Fe dose. Following several warnings such a useless commerecial oral iron preparation was finally withdrawn from the market. The iron from any high-molecular weight carbohydrate complex of ferric hydroxide has to be suspected to be poorly absorbed and therefore therapeutical useless, unless the opposite has been demonstrated with a reliable bioassay (59Fe absorption whole-body retention and hemoglobin regeneration test). A low-molecular weight so-called ferric hydroxide-fructose complex was shown to contain iron of more or less the same poor bioavailability as contained in ferric chloride since the iron from ferrous sulfate was about 5 times better absorable. The good absorption of ferrous sulfate iron was not further augmented by even very large oral doses of fructose since this carbohydrate did not improve the ferrous iron absorption at a fructose: Fe molar ratio of 106:1. Trivalent iron in simple compounds like ferric ammonium citrate or in low- and high-molecular weight carbohydrate complexes of ferric hydroxide is so poorly available for intestinal iron absorption in man that it cannot be used for a fast and reliable oral iron therapy with reasonably low doses as it can be easily practised with quick-lease preparations of ferrous sulfate at a 100 mg Fe2     

Role of ascorbic acid in transferrin-independent reduction and uptake of iron by U-937 cells

The role of ascorbic acid in transferrin-independent ferric iron reduction and uptake was evaluated in cultured U-937 monocytic cells. Uptake of 55Fe by U-937 cells was doubled by 100 microM extracellular ascorbate, and by pre-incubation of cells with 100 microM dehydroascorbic acid, the two-electron-oxidized form of ascorbate. Reduction of extracellular ferric citrate also was enhanced by loading the cells with dehydroascorbic acid. Dehydroascorbic acid was taken up rapidly by the cells and reduced to ascorbate, such that the latter reached intracellular concentrations as high as 6 mM. However, some ascorbate did escape the cells and could be detected at concentrations of up to 1 microM in the incubation medium. Further, addition of ascorbate oxidase almost reversed the effects of dehydroascorbic acid on both 55Fe uptake and ferric citrate reduction. Thus, it is likely that extracellular ascorbate reduced ferric to ferrous iron, which was then taken up by the cells. This hypothesis also was supported by the finding that during loading with ferric citrate, only extracellular ascorbate increased the pool of intracellular ferrous iron that could be chelated with cell-penetrant ferrous iron chelators. In contrast to its inhibition of ascorbate-dependent ferric iron reduction, ascorbate oxidase was without effect on ascorbate-dependent reduction of extracellular ferricyanide. This indicates that the cells use different mechanisms for reduction of ferric iron and ferricyanide. Therefore, extracellular ascorbate derived from cells can enhance transferrin-independent iron uptake by reducing ferric to ferrous iron, but intracellular ascorbate neither contributes to this reduction nor modifies the redox status of intracellular free iron.     

Effects of ascorbic acid on interactions between ciprofloxacin and ferrous sulphate, sodium ferrous citrate or ferric pyrophosphate, in mice

The absorption of ciprofloxacin has been reported to be impaired by concomitant administration of ferrous sulphate. The effects of sodium ferrous citrate and ferric pyrophosphate, which have been used as extensively as ferrous sulphate, on the absorption of ciprofloxacin were compared with that of ferrous sulphate. The effects of ascorbic acid on the interactions between ciprofloxacin and each iron compound were studied in mice. Mice were treated orally with ciprofloxacin (50 mg kg(-1)) alone, the iron compound (ferrous sulphate, sodium ferrous citrate or ferric pyrophosphate; 50 mg elemental iron kg(-1)) alone, ciprofloxacin with each iron compound or ciprofloxacin in combination with each iron compound and ascorbic acid (250 mg kg(-1)). The maximum serum concentration of ciprofloxacin was significantly (P < 0.01) reduced from 1.15+/-0.11 microg mL(-1) (ciprofloxacin alone) to 0.17+/-0.01, 0.27+/-0.01 or 0.28+/-0.02 microg mL(-1), respectively, when ferrous sulphate, sodium ferrous citrate or ferric pyrophosphate was administered along with ciprofloxacin. The addition of ascorbic acid did not affect the inhibitory effects of each iron compound on the absorption of ciprofloxacin. Ciprofloxacin did not affect the variation of serum iron levels after administration of each iron compound. The addition of ascorbic acid significantly (P < 0.01) enhanced the increase in serum iron concentration after administration of sodium ferrous citrate, showing an increase from 270+/-6 microg dL(-1) to 463+/-11 microg dL(-1) compared with an increase from 248+/-8 microg dL(-1) to 394+/-18 microg dL(-1) after administration of sodium ferrous citrate alone. Ascorbic acid also caused a significant (P < 0.01) increase in serum iron concentration from 261+/-16 microg dL(-1) to 360+/-12 microg dL(-1) after administration of ferric pyrophosphate, although it did not affect the levels after ferrous sulphate administration. The results suggest that sodium ferrous citrate and ferric pyrophosphate should not be administered with ciprofloxacin (as for ferrous sulphate) and that sodium ferrous citrate is converted to the ferric form more easily than ferrous sulphate. This difference in convertibility might contribute to a clinical difference between sodium ferrous citrate and ferrous sulphate.     

Effect of iron liposomes on anemia of inflammation

Supplementation with iron-fortified foods is an effective method for treating iron deficiency diseases. However, traditional iron agents used to treat anemia of inflammation (AI) have little effect. In this study, two types of iron liposomes, heme liposomes (HEME-LIP) and ferric citrate liposomes (FAC-LIP), were prepared by the rotary-evaporated film-ultrasonication method, and the encapsulation efficiencies, microstructures, size distributions and zeta potentials were assessed. Both types of iron liposomes showed stable physical characteristics. When used to treat rat models of AI, FAC-LIP and HEME-LIP could increase serum iron levels by 119% and 54% higher than did ferric citrate (FAC) and heme, respectively. Furthermore, the hepcidin, a key regulator of iron homeostasis was up-regulated by these iron liposomes, especially by HEME-LIP. These results indicate that the absorption of iron liposomes was improved over that of unencapsulated iron agents. Thus, iron liposomes may be used to fortify food in treating iron deficiency diseases, especially AI.     

In vivo behaviour of low molecular weight iron complexes.

The in vivo distribution in mice of ferric citrate, ferric beta-glycerophosphate and ferric lactate complexes has been studied. There is a relationship between the 59Fe uptake by various tissues and the physicochemical characteristics of the complexes. Ferric lactate seems a useful preparation for iron deficiency therapy.     

Dual mechanism of mangiferin protection against iron-induced damage to 2-deoxyribose and ascorbate oxidation.

We studied mangiferin effects on the degradation of 2-deoxyribose induced by Fe(III)-EDTA/citrate plus ascorbate, in relation to ascorbate oxidation (measured at 265 nm). Results revealed that mangiferin was equally effective in preventing degradation of both 15 and 1.5 mM 2-deoxyribose. At a fixed Fe(III) concentration, increasing the concentration of ligands (either EDTA or citrate) caused a significant reduction in the protective effects of mangiferin. Interestingly, mangiferin strongly stimulated Fe(III)-EDTA ascorbate oxidation, but inhibited it when citrate was used as iron co-chelator. Mangiferin stimulated O2 consumption due to Fe(II) (formed by Fe(III) ascorbate reduction) autoxidation when the metal ligand was EDTA, but inhibited it when citrate was used. These results suggest that mangiferin removes iron from citrate, but not from EDTA, forming an iron-mangiferin complex that cannot induce ascorbate oxidation effectively, thus inhibiting iron-mediated oxyradical formation. Taken together, these results indicate that mangiferin works mainly by a mechanism different from the classical hydroxyl radical scavengers, keeping iron in its ferric form, by complexing Fe(III), or stimulating Fe(II) autoxidation.     

Effects of iron and iron chelation in vitro on mucosal oxidant activity in ulcerative colitis

BACKGROUND: Reactive oxygen species may be pathogenic in ulcerative colitis. Oral iron supplements anecdotally exacerbate inflammatory bowel disease and iron levels are elevated in the inflamed mucosa. Mucosal iron may enhance hydroxyl ion production via Fenton chemistry. Conversely, the iron chelator, desferrioxamine, is reportedly beneficial in Crohn's disease. AIMS: To assess the in vitro effects of exogenous iron and of iron chelators on the production of reactive oxygen species by colonic biopsies from normal control subjects and patients with ulcerative colitis. METHODS: Luminol-amplified chemiluminescence was used to measure mucosal reactive oxygen species production both before and after addition in vitro of ferric citrate (100 microM), desferrioxamine (1 mM) and 1,10-phenanthroline (1 mM). RESULTS: Ferric citrate had no effect on the chemiluminescence produced by human colonic mucosa. However, desferrioxamine and phenanthroline reduced chemiluminescence by 47% (n=7, P=0.018) and by 26% (n=10, P=0.005), respectively, in inactive ulcerative colitis, and by 44% (n=9, P=0. 008) and 42% (n=11, P=0.006) in active disease. CONCLUSION: The lack of effect of ferric citrate suggests that sufficient free iron is already present in inflamed biopsies to drive the Fenton reaction maximally. The effects of desferrioxamine and 1,10-phenanthroline on the chemiluminescence of biopsies from patients with ulcerative colitis suggest that a clinical trial of topical iron chelation in active disease is indicated.     

Mössbauer spectroscopy indicates that iron in an aluminosilicate glass phase is the source of the bioavailable iron from coal fly ash

Iron speciation by M?ssbauer spectroscopy indicates that ferric iron in an aluminosilicate glass phase is the source of the bioavailable iron in coal fly ash and that this iron species is associated with combustion particles, but not with crustal dust derived from soil minerals. Urban particulate has been shown to be a source of bioavailable iron and has been shown to be able to induce the formation of reactive species in cell culture experiments. Crustal dust and laboratory-generated coal fly ash have been studied as surrogates for two sources of metal-bearing particles in ambient air. As much as a 60-fold difference in the amount of iron mobilized by the chelator citrate was observed between fly ash and crustal dust samples with similar total iron contents. The extent of iron mobilization by citrate in vitro has been shown to correlate with indirect measures of excess iron in cultured cells and with assays for reactive oxygen species generation in vitro. M?ssbauer spectroscopy of coal fly ash, before and after treatment with the chelator desferrioxamine B, showed that the iron in an aluminosilicate glass phase was preferentially removed. The removal of the glass-phase iron greatly reduced the amount of iron that could be mobilized by citrate and prevented the particles from inducing interleukin-8 in cultured human lung epithelial (A549) cells. Ferric iron in aluminosilicate glass is associated with particles formed at high temperatures followed by rapid cooling. The observation that ferric iron in aluminosilicate glass is the source of bioavailable iron in coal fly ash suggests that particles from ambient sources and other specific combustion sources should be examined for the presence of this potential source of bioavailable iron.     

Assessment of the extent of oxidative stress induced by intravenous ferumoxytol, ferric carboxymaltose, iron sucrose and iron dextran in a nonclinical model

Intravenous (i.v.) iron is associated with a risk of oxidative stress. The effects of ferumoxytol, a recently approved i.v. iron preparation, were compared with those of ferric carboxymaltose, low molecular weight iron dextran and iron sucrose in the liver, kidneys and heart of normal rats. In contrast to iron sucrose and ferric carboxymaltose, low molecular weight iron dextran and ferumoxytol caused renal and hepatic damage as demonstrated by proteinuria and increased liver enzyme levels. Higher levels of oxidative stress in these tissues were also indicated, by significantly higher levels of malondialdehyde, significantly increased antioxidant enzyme activities, and a significant reduction in the reduced to oxidized glutathione ratio. Inflammatory markers were also significantly higher with ferumoxytol and low molecular weight iron dextran rats than iron sucrose and ferric carboxymaltose. Polarographic analysis suggested that ferumoxytol contains a component with a more positive reduction potential, which may facilitate iron-catalyzed formation of reactive oxygen species and thus be responsible for the observed effects. Only low molecular weight iron dextran induced oxidative stress and inflammation in the heart.     

晚期肾疾病病人的下肢不宁综合征的治疗进展

下肢不宁综合征是晚期肾疾病病人常见的并发症之一，是一种神经系统感觉运动障碍性疾病，该病可严重影响病人的睡眠，显著降低其生活质量。尽管目前尚无有效的治疗方法，但多巴胺类药物有良好的治疗效果，其中反跳和症状加重是左旋多巴的主要不良反应。多巴胺激动药不良反应少，已成为治疗该病的主要药物。阿片类、抗惊厥药和苯二氮革类药物也是常用的治疗药物。因下肢不宁综合征病人血清铁转移至脑中枢发生障碍，部分病人可通过补充铁剂来治疗。     

A 13-week subchronic toxicity study of ferric citrate in F344 rats

Ferric citrate has been used as a food additive for supplementation of iron. We performed a 13-week subchronic toxicity study of ferric citrate in F344 rats with oral administration in the diet at concentrations of 0%, 0.25%, 1.0%, and 4.0%. Reduction of body weight gain was noted in 4.0% males and females. On hematology assessment, decreases of red blood cells and lymphocytes and increases of platelets and eosinophils were noted in 4.0% males and females. Serum biochemistry demonstrated increased iron and decreased total protein and transferrin in both sexes treated with 4.0% ferric citrate. In addition, an increase of serum inorganic phosphorus levels was noted in 4.0% females. Regarding organ weights, an increase of relative spleen weights was detected in 4.0% males and females and a decrease of absolute and relative heart weights in 4.0% females. On histopathological assessment, colitis with infiltration of eosinophils and hyperplasia of mucosal epithelium, eosinophilic infiltration in mesenteric lymph nodes, and increased hemosiderosis in spleen were observed as treatment-related toxicological changes in 4.0% males and females. Based on the results, the no-observed-adverse-effect level (NOAEL) of ferric citrate was estimated to be 1.0% (596 mg/kg bw/day for males and 601 mg/kg bw/day for females).     

Protective effect of naringin, a bioflavonoid on ferric nitrilotriacetate-induced oxidative renal damage in rat kidney

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces acute proximal tubular necrosis as a consequence of lipid peroxidation and oxidative tissue damage that eventually leads to high incidence of renal adenocarcinomas in rodents. This study was designed to investigate the effect of Naringin, a bioflavonoid with anti-oxidant potential, on Fe-NTA-induced nephrotoxicity in rats. One hour after a single intra-peritoneal (i.p.) injection of Fe-NTA (8 mg iron/kg body weight), a marked deterioration of renal architecture and renal function was observed. Fe-NTA induced a significant renal oxidative stress, demonstrated by elevated thiobarbituric acid reacting substances (TBARS) and reduction in activities of renal catalase, superoxide dismutase, and glutathione reductase. Pre-treatment of animals with Naringin, 60 min before Fe-NTA administration, markedly attenuated renal dysfunction, morphological alterations, reduced elevated TBARS, and restored the depleted renal anti-oxidant enzymes. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction and suggest a protective effect of Naringin on Fe-NTA-induced nephrotoxicity in rats.     

Quercetin, a bioflavonoid, attenuates ferric nitrilotriacetate-induced oxidative renal injury in rats

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces acute proximal tubular necrosis as a consequence of lipid peroxidation and oxidative tissue damage, that eventually leads to high incidence of renal adenocarcinomas in rodents. This study was designed to investigate the effect of quercetin, a bioflavonoid with antioxidant potential, on Fe-NTA-induced nephrotoxicity in rats. One hour after a single intraperitoneal (i.p.) injection of Fe-NTA (8 mg iron/kg), a marked deterioration of renal architecture and renal function was observed. Fe-NTA induced a significant renal oxidative stress demonstrated by elevated thiobarbituric acid reacting substances (TBARS) and reduction in activities of renal catalase, superoxide dismutase and glutathione reductase. Pretreatment of animals with quercetin (2 mg/kg, i.p.) 30 minutes before Fe-NTA administration markedly attenuated renal dysfunction, morphological alterations, reduced elevated TBARS and restored the depleted renal antioxidant enzymes. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of quercetin on Fe-NTA-induced nephrotoxicity in rats.     

The importance of reductive mechanisms for intestinal uptake of iron from ferric maltol and ferric nitrilotriacetic acid (NTA)

Intestinal iron absorption is thought to proceed with iron mainly in the ferrous form, yet the novel iron complex, ferric maltol is an effective oral preparation. Although possessing a high oil: water partition coefficient, ferric maltol does not diffuse across the intestine but donates its iron to the endogenous uptake system. Reduction of the ferric iron in the gut lumen appears to precede iron uptake both from ferric maltol and from ferric nitrilotriacetic acid (NTA) which is a non-penetrating iron ligand. Uptake of radiolabelled iron (59Fe) into isolated fragments of rat small intestine was inhibited by the ferrous chelator, bathophenanthroline sulphonate (BPS) and enhanced at low concentrations by the reducing agent ascorbic acid. Spectrophotometric evidence was obtained that ferrous ions are generated from these ferric complexes in the presence of ascorbic acid and other reducing agents. The rate of ferrous ion formation was independent of ferric maltol concentration at low ascorbic acid levels and decreased with increasing ferric maltol concentration at higher levels of ascorbate. Maltol has a high affinity for ferric ions and may delay reduction at higher concentrations. By contrast, a higher rate of ferrous ion generation was seen with ferric NTA and this increased with iron ligand concentration. Washings from the intestinal lumen also brought about ferrous ion formation from these ferric ligands. Gel filtration revealed these reducing factors to be of low molecular weight. The washings, however, interfered with 59Fe uptake into the isolated fragments, but when reducing fractions only from the filtered washings were used, enhanced iron uptake was seen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of type 2 diabetic nephropathy by blockade of the renin-angiotensin system: a comparison of angiotensin-converting-enzyme inhibitors and angiotensin receptor antagonists

Type 2 diabetes is the most prevalent form of diabetes mellitus worldwide and associated diabetic nephropathy is the most common cause of end-stage renal disease in the USA. Lowering blood pressure and controlling glucose slows the progression to end-stage renal disease or death. Although angiotensin-converting-enzyme inhibitors reduce proteinuria, their effects to slow progression to end-stage renal disease have not been clearly demonstrated in type 2 diabetic nephropathy. Recent clinical trials with angiotensin AT(1) receptor antagonists demonstrate that they reduce proteinuria, stabilize renal function and slow the progression of nephropathy to end-stage renal disease in patients with type 2 diabetes. These are significant benefits beyond those associated with conventional therapy and blood pressure control.     

Nephrotoxicity and its prevention by catechin in ferric nitrilotriacetate promoted oxidative stress in rats

Intraperitoneal injection of ferric nitrilotriacetate (Fe-NTA) to rats and mice results in iron-induced free radical injury and cancer in kidneys. This study was designed to investigate the effect of catechin, a bioflavonoid with antioxidant potential, on Fe-NTA-induced nephrotoxicity in rats. Four groups were employed in the present study. Group I served as control group, Group II animals received Fe-NTA (8 mg iron/kg body weight i.p.), Group III animals were given 40 mg/kg catechin p.o. twice a day for 4 days and on the 5th day Fe-NTA was challenged, and Group IV animals received catechin alone for 4 days. Renal function was assessed by measuring plasma creatinine and blood urea nitrogen. The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, glutathione reductase and superoxide dismutase. One hour after a single intraperitoneal (i.p.) injection of Fe-NTA (8 mg iron/kg), a marked deterioration of renal architecture, renal function and severe oxidative stress was observed. Pretreatment of animals with catechin markedly attenuated renal dysfunction, reduced elevated thiobarbituric acid reacting substances (TBARS), restored the depleted renal antioxidant enzymes and normalized the renal morphological alterations. These results clearly demonstrate the role of oxidative stress and its relation to renal dysfunction, and suggest a protective effect of catechin on Fe-NTA-induced nephrotoxicity in rats.     

Ferric citrate CYP2E1-independently promotes alcohol-induced apoptosis in HepG2 cells via oxidative/nitrative stress which is attenuated by pretreatment with baicalin

In the case of alcoholic liver injury, an iron overload is always present. Both alcohol and iron can individually induce oxidative stress in liver. However, the combined effect of physiological concentrations of alcohol and iron on oxidative stress in hepatocytes remains unknown. Baicalin has been demonstrated to be an antioxidant or iron chelator in animal experiments. In this study, we investigated the injury to hepatocytes CYP2E1-independently induced by the combination of alcohol and iron and the protective effect of baicalin. Compared with cells treated with ethanol alone, ferric citrate enhanced the accumulation of reactive oxygen and nitrogen species, increased the occurrence of protein carbonylation/nitration and the levels of 4-hydroxy-2-nonenal, changed the distribution of iNOS, and eventually resulted in apoptosis. However, pretreatment with baicalin inhibited the oxidative stress induced by the combination of alcohol and iron, mainly by chelating iron. Our findings therefore suggest that iron could CPY2E1-independently enhance the oxidative stress induced by alcohol, which probably contributes to the pathogenesis of alcoholic liver disease. Baicalin is a promising phytomedicine for preventing alcoholic liver disease.     

Nuclear aberrations and micronuclei induction in the digestive tract of mice treated with different iron salts

Toxic effects of ferrous sulfate and of ferric chloride were determined in the gastrointestinal tract by measuring the induction of nuclear aberrations and micronuclei. In fasting animals ferric chloride induced a dose-related increase of nuclear aberrations in the stomach, whereas ferrous sulfate was not active. In normally feeding animals no increase of nuclear aberrations was observed. The effects of the iron compounds on the duodenum were minimal. In fasting animals a dose-related increase of nuclear aberrations was observed at the level of the colon, with no clear difference between ferrous and ferric compounds. A modest increase of nuclear aberrations of the colon was seen in feeding animals only with ferrous sulphate. By intrarectal administration, nuclear aberrations were induced especially by ferric chloride. An increase of the frequency of micronuclei was not observed at the level of the stomach, duodenum and colon, with the exception of ferric chloride, that induces a significant, although small increase of colon micronuclei when administered intra-rectally. The data demonstrate that iron compounds have an intrinsic cellular toxicity when not administered with food, but do not seem to carry any genotoxic potential for the gastrointestinal tract.