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Biomedical subjects

D M Templeton

Publications and source records attributed to D M Templeton.

At least 19 recordsLinked to original sources
PubMed1997

Characterization of Fe2+ and Fe3+ transport by iron-loaded cardiac myocytes.

Plasma iron overload causes cardiac iron accumulation leading to toxicity and organ failure. In order to understand the basis of iron acquisition, we examined mechanisms of Fe3+ and Fe2+ uptake in control and iron-loaded cardiomyocyte cultures. Iron loading increased rates of Fe3+ and Fe2+ uptake, primarily by increasing Vmax. Inhibition of Fe3+ transport by impermeable Fe2+ chelators and the presence of a cell surface ferricyanide reductase activity are consistent with a role for redox cycling in Fe3+ uptake. However, flavoproteins and copper-dependent oxidases known to be required for redox-active iron transport in yeast do not appear to be involved in iron uptake by cardiac myocytes, nor do the abundant cardiac L-type Ca2+ channels. The data suggest that both redox states of iron contribute to cardiac iron accumulation in iron overload.

Animals↗
PubMed1996

Heparin inhibits mitogen-activated protein kinase-dependent and -independent c-fos induction in mesangial cells.

Heparin suppresses mitogenic responses in renal mesangial cells, and when quiescent mesangial cells are stimulated with serum, heparin blocks the induction of c-fos seen at 15 min. Because heparin is taken up by cells over a much longer time course, we addressed mechanisms whereby extracellular heparin might suppress c-fos induction at such early times. Quiescent cells were treated with serum, 12-O-tetradecanoylphorbol-13-acetate, or low concentrations of Ca2+ ionophores that produced increases in intracellular Ca2+ concentration ([Ca2+]i) in the physiological range. Each treatment caused an increase in c-fos mRNA, but they did so by different mechanisms. Serum activated mitogen-activated protein kinase (MAPK) and increased [Ca2+]i without affecting protein kinase C. Activation of protein kinase C with phorbol ester activated MAPK without much effect on [Ca2+]i. Ionophores increased [Ca2+]i without affecting basal levels of protein kinase C or MAPK. Heparin (1 microg/ml) suppressed the induction of c-fos initiated by all three treatments. It did not affect the activity of protein kinase C, but inhibited activation of MAPK by either serum or phorbol ester, suggesting a common site of action at or below the probable convergence of the induced signals at Ras/Raf-1 activation. Heparin also inhibited the serum-stimulated entry of extracellular Ca2+ to the same extent as verapamil, consistent with the ability of verapamil to block L-type Ca2+ channels and the known presence of these channels in mesangial cells. However, this effect does not appear to be related to heparin's ability to inhibit induction of c-fos. First, verapamil had no effect on induction of c-fos by serum. Second, heparin had no effect on changes in [Ca2+]i achieved by ionophores. We conclude that heparin suppresses induction of c-fos in mesangial cells by blocking at least two different points in signal transduction cascades, one upstream of MAPK and the other independent of MAPK, but dependent on intracellular Ca2+.

Amino Acid Sequence↗
PubMed1996

Calcium-independent effects of cadmium on actin assembly in mesangial and vascular smooth muscle cells.

Several metal ions are known to cause depolymerization of the actin cytoskeleton under some circumstances. We found that in renal mesangial and vascular smooth muscle cells, micromolar concentrations of Cd2+ result in loss of phalloidinstainable filamentous (F-) actin. The decrease in F-actin was not accompanied by a corresponding increase in G-actin. The decrease in total actin could be accounted for in part by an inhibition by Cd2+ of total protein (and actin) synthesis after 6 to 8 h without an effect on actin degradation, and the equilibrium between F- and G-actin was shifted to maintain near-constant levels of G-actin. However, Cd2+ caused significant decreases in F-actin at earlier times, indicating effects on the polymerization equilibrium independent of those on actin synthesis. Only picomolar concentrations of free intracellular Cd2+ occur in these experiments. However, it is this Cd2+ pool which is responsible for F-actin depolymerization because equal cellular concentrations of cadmium delivered as Cd-metallothionein have no effect. The effect is also very specific for Cd2+ and under the same conditions neither Mg2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, nor Hg2+ result in any loss of F-actin. Addition of Cd2+ to mesangial and vascular smooth muscle cells had no immediate effect on free intracellular calcium concentrations ([Ca2+]i) even though Ca(2+)-signalling pathways were intact as shown with vasopressin and endothelin. Exposure to 10 microM CdCl2 for 8 h nevertheless caused an increase in [Ca2+]i to > 250 nM and increases in [Ca2+]i achieved with ionophores alone were sufficient to decrease F-actin concentrations. However, a rise in [Ca2+]i is not necessary for actin depolymerization. Depletion of cellular Ca2+ by treatment with thapsigargin did not protect F-actin against Cd2+; the effect of Cd2+ was enhanced in cells unable to increase their [Ca2+]i. We conclude that depolymerization of F-actin by Cd2+ in smooth muscle and mesangial cells is metal-specific, Ca(2+)-independent, and accompanied by a depletion of total actin protein.

Actins↗
PubMed1996

Cellular factors mediate cadmium-dependent actin depolymerization.

Cadmium exposure produces depolymerization of the actin cytoskeleton in several cultured cell lines, and we have previously shown that in renal mesangial cells this effect is caused by picomolar concentrations of cytosolic Cd2+. The present study was undertaken to explore further the basis of this action of Cd2+. Skeletal muscle actin was labeled with pyrene and rates of polymerization and depolymerization were followed in vitro by changes in fluorescence. Concentrations of 100 microM or higher Cd2+ increased the rate of polymerization while lower concentrations stabilized actin filaments. Because this is in contrast to the observation that Cd2+ favors depolymerization in cultured mesangial cells, we examined the role of cellular factors in modifying the actions of Cd2+ on the polymerization/depolymerization equilibrium. Inclusion in the in vitro polymerization assay of cytosol from mesangial cells pre-treated with 5 microM CdCl2 caused a decrease in the rate of polymerization and an increase in the rate of depolymerization, relative to cytosol from control cells. EGTA normalized these rates, indicating involvement of Ca2+-dependent factors. Likewise, cytoskeleton from Cd2+-treated cells caused a Ca2+-dependent decrease in actin polymerization. Ligand blotting with [125I]actin revealed loss of binding of a 93-kDa protein from the cytosol and an increase in binding of a 49-kDa protein in the cytoskeletal fraction upon treatment of mesangial cells with Cd2+. Based on their electrophoretic mobility and Ca2+ dependence of actin binding these are tentatively identified as members of the gelsolin and severin families, respectively. Thus, Cd2+ may exert its effect on the mesangial cell cytoskeleton by altering the levels or actin-binding activity of actin-associated proteins.

Actins↗
PubMed1996

Posttranscriptional effects of glucose on proteoglycan expression in mesangial cells.

Hyperglycemic conditions are known to increase mRNA and protein levels of several extracellular matrix molecules in cultured mesangial cells, but accompanying increases in proteoglycan mRNA have not been found, and there are discrepant reports of normal or decreased proteoglycan synthesis with or without undersulfation in diabetic kidneys and hyperglycemic cultures. We examined the effects in proliferating cells of glucose on [35S]Sulfate incorporation into heparan and dermatan sulfates and on mRNA levels of decorin, biglycan, and basement membrane perlecan. In both mesangial cells and vascular smooth muscle cells, 30 mmol/L glucose caused a decrease of 15% to 25% in the amount of sulfate incorporated into each proteoglycan in cultures confluent for 1 to 4 days, compared with 10 mmol/L glucose. The effect showed no specificity for the class of proteoglycan and was not a consequence of changes in total protein synthesis, which increased, or cell proliferation, which was unaffected. No decrease in charge density of any of the proteoglycan fractions was observed by ion-exchange chromatography. Therefore, the decrease in labeling was due to a decrease in synthesis and not undersulfation. mRNA levels for biglycan and perlecan increased slightly and transiently, and these changes cannot account for the decreased synthesis. Decorin mRNA was detected only in smooth muscle cells, where it and biglycan were differentially affected by glucose, apparently at the transcriptional level; stabilities of the two messages were unaffected by glucose. Although transforming growth factor-beta 1 (TGF-beta 1) mRNA levels increased in response to glucose, the cytokine did not appear to regulate proteoglycan synthesis, because structural changes in proteoglycans elicited by addition of TGF-beta 1 to the culture medium did not occur in the hyperglycemic cultures. On the other hand, inhibition and downregulation of protein kinase C (PKC), while decreasing net sulfate incorporation into mesangial cell proteoglycans, prevented the effect of high glucose. We conclude that a high glucose concentration causes a general decrease in the synthesis of all classes of proteoglycans at a posttranscriptional level, and can do so without affecting the charge density of individual proteoglycan molecules.

Animals↗
PubMed1996

Sample collection guidelines for trace elements in blood and urine. IUPAC Commission of Toxicology.

This paper presents an organized system for element-specific sample collection and handling of human blood (whole blood, serum or plasma, packed cells or erythrocytes) and urine also indicating a proper definition of the subject and sample. Harmonized procedures for collection, preparation, analysis and quality control are suggested. The aim is to assist scientists worldwide to produce comparable data which will be useful on a regional, national and international scale. The guidelines are directed to the elements aluminium, arsenic, cadmium, chromium, cobalt, copper, lead, lithium, manganese, mercury, nickel, selenium and zinc. These include the most important elements measured for their occupational or clinical significance, and serve as examples of principles that will guide development of methods for other elements in the future.

Blood Specimen Collection↗
PubMed1996

Inhibition of mitogenesis and c-fos induction in mesangial cells by heparin and heparan sulfates.

When rat renal mesangial cells (RMC) or vascular smooth muscle cells are released from quiescence by serum stimulation they express c-fos mRNA transiently at 30 to 60 minutes and progress in synchrony to S phase. Heparin causes significant suppression of [3H]-thymidine incorporation into DNA in S phase and a decrease and delay of entry of cells into S/G2. Added at the time of serum stimulation, heparin (1 microgram/ml or less) causes a decrease in the subsequent expression of c-fos mRNA in RMC, and a similar effect is observed with heparan sulfate chains isolated from RMC-cultures themselves. Although these cells internalize and degrade heparin, the timing of the maximal effect indicates an extracellular action of heparin. In keeping with this idea, 125I-heparin binds specifically to a single class of high affinity sites on the cell surface. The effect of heparin on c-fos induction may be independent of interaction with cytokines or cytokine receptors; its magnitude is not diminished when heparin-binding substances are removed from serum by heparin-Sepharose. Furthermore, direct activation of protein kinase C (PKC) with a phorbol ester in the absence of serum likewise induces c-fos and 1 microgram/ml heparin inhibits this response by 65%. Phorbol ester caused an increase in the proportion of histone H1-active PKC associated with the cell membrane fraction, from approximately 25% to 70% of total activity. Heparin affected neither the total activity of the kinase nor the proportion associated with the membrane. When PKC was inhibited with staurosporine, only very low levels of c-fos were induced by serum. We conclude that low concentrations of heparin and heparan sulfate suppress the mitogenic response of mesangial cells to serum and inhibit c-fos mRNA induction through an effect of cell surface-bound glycosaminoglycan on a signalling pathway downstream of PKC.

Animals↗
PubMed1996

Collagen type I enhances endothelin-mediated contraction and induces nonproliferating phenotype in mesangial cells.

Accumulation of glomerular extracellular matrix is a characteristic accompaniment of mesangial cell proliferation in progressive renal disease. We examined how growth on several matrices affected the proliferative phenotype of cultured rat mesangial cells. Compared with growth on plastic, Matrigel, or mesangial matrix, collagen type I caused a decreased cell number at 72 h, decreased total DNA per culture, and a decrease in the incorporation of [3H]thymidine during S phase in cells released from quiescence. These antiproliferative and antimitogenic effects of collagen type I required growth on a collagen gel; soluble collagen or collagen fragments were without effect. Because a number of agents elicit both proliferative and contractile responses in mesangial cells, we examined the effect of growth on collagen on contractility. Compared with plastic, cells grown on collagen type I were more contractile, showed a higher Ca2+ signal in response to endothelin, and responded to endothelin with a more rapid myosin light-chain kinase-dependent phosphorylation of myosin light chain. We conclude that growth on a collagen type I gel uncouples contractility from a proliferative response in mesangial cells, suppressing proliferation while enhancing contraction and Ca2+ signaling in response to endothelin.

Alkaloids↗
PubMed1995

Modulation by iron loading and chelation of the uptake of non-transferrin-bound iron by human liver cells.

Hepatic non-transferrin-bound Fe (NTBI) flux and its regulation were characterized by measuring the uptake of Fe from [59Fe]/nitrilotriacetate (NTA) complexes in control and Fe-loaded cultures of human hepatocellular carcinoma cells (HepG2). Exposure to ferric ammonium citrate (FAC) for 1 to 7 days resulted in a time- and dose-dependent increase in the rate of NTBI uptake. In contrast to previous studies showing a dependence of the rate of Fe uptake on extracellular Fe, this was positively correlated with total cellular Fe content. The Fe3+ chelating agents deferoxamine (DFO), 1,2-dimethyl-3-hydroxypyrid-4-one (CP 020) and 1,2-diethyl-3-hydroxypyrid-4-one (CP 094) prevented or diminished the increase in NTBI transport when present during Fe loading and reversed the stimulation in pre-loaded cells in relation to their abilities to decrease intracellular iron. Although saturation of the Fe uptake process was not achieved in control cells, kinetic modelling to include linear diffusion-controlled processes yielded estimated parameters of Km = 4.3 microM and Vmax = 2.6 fmol/micrograms protein/min for the underlying process. There was a significant increase in the apparent Vmax (31.2 fmol/micrograms protein per min) for NTBI uptake in Fe-loaded cells, suggesting that Fe loading increases the number of a rate-limiting carrier site for Fe. Km also increased to 15.2 microM, comparable to values reported when whole liver is perfused with FeSO4. We conclude that HepG2 cells possess a transferrin-independent mechanism of Fe accumulation that responds reversibly to a regulatory intracellular Fe pool.

Biological Transport↗
PubMed1995

Iron-chelation therapy with oral deferiprone in patients with thalassemia major.

BACKGROUND: To determine whether the orally active iron chelator deferiprone (1,2-dimethyl-3-hydroxy-pyridin-4-one) is efficacious in the treatment of iron overload in patients with thalassemia major, we conducted a prospective trial of deferiprone in 21 patients unable or unwilling to use standard chelation therapy with parenteral deferoxamine. METHODS: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens or magnetic-susceptibility measurements. Detailed clinical and laboratory studies were used to monitor safety and compliance. RESULTS: The patients received deferiprone therapy for a mean (+/-SE) of 3.1 +/- 0.3 years. Ten patients in whom previous chelation therapy with deferoxamine had been ineffective had initial hepatic iron concentrations of at least 80 mumol per gram of liver, wet weight -- values associated with complications of iron overload. Hepatic iron concentrations decreased in all 10 patients, from 125.3 +/- 11.5 to 60.3 +/- 9.6 mumol per gram (P < 0.005), with values that were less than 80 mumol per gram in 8 of the 10 patients (P < 0.005). In all 11 patients in whom deferoxamine therapy had previously been effective, deferiprone maintained hepatic iron concentrations below 80 mumol of iron per gram. CONCLUSIONS: Oral deferiprone induces sustained decreases in body iron to concentrations compatible with the avoidance of complications from iron overload. The risk of agranulocytosis associated with deferiprone may restrict its administration to patients who are unable or unwilling to use deferoxamine.

Administration, Oral↗
PubMed1994

Reversed-phase high-performance liquid chromatography of non-transferrin-bound iron and some hydroxypyridone and hydroxypyrone chelators.

The pursuit of orally available Fe(III) chelating agents has resulted in several clinical trials of 1,2-dimethyl-3-hydroxypyrid-4-one (CP20). Chromatography of this and related Fe chelators on silica-based columns has proven difficult due to unwanted interactions with the stationary phase, including with contaminating Fe bound to silanol groups. By addition of Fe3+ (50 microM ferric ammonium citrate) to an acidified aqueous mobile phase, we have successfully separated a series of hydroxypyridones-including CP20-and the related pyrones maltol and ethylmaltol by HPLC on microBondapak C18. Complexation occurs with these agents even at low pH, and they elute in an order consistent with the partition coefficients of their Fe(III) complexes. By the reverse strategy of adding ethylmaltol to the mobile phase, chelatable Fe was chromatographed and the peak response at 500 nm was linear down to a detection limit below 0.5 microM. This method was applied to pooled serum and to serum spiked with Fe after filtration at 10 kDa cut-off. The direct determination of non-transferrin-bound Fe at micromolar concentrations in serum is possible with this approach.

Chromatography, High Pressure Liquid↗
PubMed1994

Uptake of non-transferrin-bound iron by both reductive and nonreductive processes is modulated by intracellular iron.

Non-transferrin-bound iron (NTBI) uptake occurs in a variety of cells by a saturable, specific and temperature-sensitive process. Our previous studies indicated that NTBI uptake by cardiac myocytes and Hep G2 cells was reversibly up-regulated by iron deposition. In the present work we have characterized this up-regulation and examined its mechanism by comparing the uptake of oxidized (Fe3+) and ascorbate-reduced (Fe2+) forms of iron. Iron loading markedly enhanced the uptake of iron both in the presence and absence of ascorbate, but the increment was greater when ascorbate was absent. This up-regulation is partially inhibited by actinomycin D and cycloheximide, indicating a requirement for protein synthesis. Uptake by the iron-loaded cells was less sensitive to thiol-alkylating agents and competing metal ions, but was more sensitive to proteolysis. Iron loading causes an increase in both Km and Vmax for uptake of both Fe2+ and Fe3+, although the values differ, suggesting distinct rate-limiting steps for uptake of Fe2+ and Fe3+. Consistent with this idea, uptake of the two ions showed differential sensitivity to thiol reagents, competing metal ions and monensin. The Fe(2+)-specific chelators bathophenanthroline disulfonate and ferrozine markedly inhibited iron uptake whether ascorbate was present or not, indicating that Fe3+ uptake is dependent on reduction to the ferrous state. This requirement for reduction was independent of the iron status of the cells, demonstrating that the process of up-regulation is not due to the appearance of a new mechanism for translocation of Fe3+ without reduction. Taken together, the evidence favors a model of NTBI transport where an obligate and rate-determining reduction of Fe3+ occurs prior to or during uptake, followed by translocation through an Fe2+ carrier. The distinct translocation mechanisms of uptake in the presence and absence of ascorbate suggest that exogenous Fe2+ does not access the carrier available to the nascent ferrous ion derived from the reductase and is consistent with close coupling between the reduction and the translocation processes. In iron-loaded cells with increased rates of NTBI transport, a similar mechanism prevails.

Alkylating Agents↗
PubMed1994

Tentative reference values for nickel concentrations in human serum, plasma, blood, and urine: evaluation according to the TRACY protocol.

Published reports of Ni concentrations in human serum or plasma, whole blood, and urine have been reviewed in order to establish a database of reference values. In keeping with the TRACY program as previously applied to Hg, reports were evaluated in the categories of description of sample population, specimen collection and processing, analytical methods, and data presentation. Based on these considerations, eight studies of Ni in serum were deemed suitable for establishing reference levels in the general population. In five of these studies, the mean values for serum Ni concentration were < 0.3 microgram/l and the upper limits were < or = 1.1 micrograms/l. Six studies of Ni in urine were found suitable, and in four of these the mean values of Ni were < or = 2.0 micrograms/l and the upper limits were < or = 6.0 micrograms/l. Fewer studies on Ni in whole blood have been reported, and the Ni content of blood remains uncertain.

Humans↗
PubMed1994

Isotope-specific analysis of Ni by ICP-MS: applications of stable isotope tracers to biokinetic studies.

Inductively coupled plasma mass spectrometry (ICP-MS) offers excellent detection limits and isotopic analysis of Ni in aqueous standards, but is prone to interferences--mainly from Ca-containing polyatomics--when biological matrices are analyzed for Ni. We have used multivariate calibration with principal components analysis (PCA) to correct for mass overlaps in serum digests. The resulting detection limit for Ni is below 1 microgram/l and the within-run imprecision is 6% at 1.46 micrograms Ni/l. In urine, the higher Ca content renders routine application of PCA problematic. We evaluated several methods of pre-concentration, and have developed a method of Ca oxalate precipitation that allows direct analysis of Ni in the diluted supernatant. The stable isotope 62Ni and the radiosotope 63Ni were co-administered i.v. to rats and the serum and urinary clearances were determined by liquid scintillation counting and ICP-MS. Ni measurements by both methods were in excellent agreement, and serum clearance fit a double exponential decay consistent with the two-compartment model of Onkelinx et al. [24]. A human volunteer ingested 61Ni (20 micrograms Ni/kg body wt.) in water after an overnight fast. Identical serum levels, peaking near 35 micrograms/l at 2 h, were measured by electrothermal atomic absorption spectrometry and ICP-MS with PCA. Urinary excretion of 61Ni measured by ICP-MS demonstrated absorption of 30% of the administered dose. We conclude that Ni isotopes can be measured in body fluids by ICP-MS at levels that allow stable isotope tracer studies in humans.

Adult↗
PubMed1994

Iron-balance and dose-response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with sickle cell disease.

Several life-threatening complications of the common disorder sickle cell disease require management with red blood cell transfusions and, hence, long-term iron-chelating therapy. The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) has not previously been determined in patients with sickle cell disease. We compared the efficacy of L1 to that of standard-dose subcutaneous deferoxamine in four regularly transfused patients with homozygous sickle cell disease, who had evidence of severe iron overload and a history of poor compliance with deferoxamine. Determination of 24-hour urinary iron excretion conducted over 5 days immediately after transfusion showed that the mean daily urinary iron excretion induced by L1 at 75 mg/kg/d (0.48 +/- 0.23 mg/kg) was equivalent to that induced by deferoxamine at 50 mg/kg/d (0.39 +/- 0.06 mg/kg). In two of three patients studied, a significant (P < .025) increase in mean daily urinary iron excretion was achieved when the dose of L1 was increased to 100 mg/kg/d. Total iron balance studies, which quantitated both urinary and stool iron excretion on L1 and deferoxamine, determined that mean total daily iron excretion induced by deferoxamine (0.88 +/- 0.05 mg/kg) was significantly greater (P < .05) than that induced by L1 (0.53 +/- 0.17 mg/kg), attributable to the significantly greater stool iron excretion during deferoxamine treatment (0.50 +/- 0.16 mg/kg/d) compared with that measured during L1 treatment (0.12 +/- 0.08 mg/kg/d, P < .01). Stool iron excretion accounted for a significantly greater percentage of total iron excretion during deferoxamine treatment (59% +/- 20%) than during L1 treatment (23% +/- 14%, P < .01). These iron balance studies are the first to compare total iron excretion induced by L1 with that achieved by deferoxamine. They demonstrate that the mean total daily iron excretion during L1 treatment (0.53 +/- 0.17 mg/kg) is sufficient to maintain net negative iron balance in most regularly transfused patients with sickle cell disease. Because long-term compliance with L1 has been shown previously to be superior to that with deferoxamine in patients with homozygous beta-thalassemia, the use of L1 should increase the long-term effectiveness of iron chelation in patients with sickle cell disease.

Administration, Oral↗
PubMed1994

Copper complexation by 3-hydroxypyridin-4-one iron chelators: structural and iron competition studies.

Clinical trials of 1,2-dimethyl-3-hydroxypyridine-4-one (1) as an orally available iron chelator are presently underway in several centers. Discrepant reports of toxicity in human and animal studies have stimulated debate on the role of iron status and the availability of iron for chelation relative to other essential elements like copper in determining the clinical effects of 1. Therefore, we investigated the ability of 1, its 1,2-diethyl analog 2, and their iron chelates to complex copper. Both compounds formed tetracoordinate 2:1 Cu(II) complexes which X-ray structure analysis showed to be planar and coordinated through the oxygen atoms of the hydroxy ketone functionality. Potentiometric analysis revealed that these complexes dominated at physiological pH, although between pH 6 and 7 approximately equal amounts of the mono and bis complexes of Cu with 1 were present at equilibrium. Comparing the stepwise formation constants deduced from the stability constants of these complexes (log beta 2 = 21.7 +/- 0.8 (1) and 20.2 +/- 2.0 (2)) with those of their Fe(III) complexes (Motekaitis,R.J.;Martell,A.E.Inorg.Chim.Acta 1991, 183,71-80) leads to a prediction of insignificant copper complexation when equimolar iron is present and dissociation products are thermodynamically unimportant. However, displacement of Fe3+ occurred from both complexes with stoichiometric amounts of Cu2+, implicating the participation of metal hydrolysis products in the equilibria. We conclude that Cu(II) complexes of the 3-hydroxypyridin-4-one chelators are stable under physiological conditions and that copper can effect displacement of iron by these agents under circumstances where hydrolysis of the metals is important.

Antithyroid Agents↗