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K Schümann

Publications and source records attributed to K Schümann.

At least 19 recordsLinked to original sources
PubMed2003

Different behaviour of 63Ni and 59Fe during absorption in iron-deficient and iron-adequate jejunal rat segments ex vivo.

Nickel exhibits low oral toxicity. It shares the absorptive pathways for iron, though there are substantial quantitative differences in handling of both metals. To analyse these differences more closely, jejunal segments from iron-deficient and iron-adequate rats were luminally perfused ex vivo with 59Fe and 63Ni at six different concentrations (1-500 micromo1/l) under steady state conditions. 59Fe over-all absorption increased 2.0-4.6-fold in iron-deficiency at luminal concentrations between 1 and 100 micromol/l, while 63Ni absorption increased to a much lower extent (2.6-fold at 1 micromol/l and 1.5-fold at higher luminal concentrations). Moreover, there was a 5-7-fold higher concentration for 63Ni in the jejunal tissue than in the absorbate at luminal concentrations above 50 micromol/l which was not observed at 1 micromol 63Ni/l and not for 59Fe. 63Ni tissue load showed a linear and a saturable fraction. In iron-deficiency the saturable 63Ni fraction increased 4-fold as compared to only 1.5-fold increments for 59Fe. Moreover, a substantially higher share of 63Ni was retained in the jejunal tissue at high as compare to low luminal concentrations after perfusion had been continued without luminal radioactivity. This was not found for 59Fe and suggests a concentration-dependent block of 63Ni export across the enterocytes' basolateral membrane. To explain these results one may speculate that 63Ni may bind more tightly to tissue ligands than 59Fe due to the higher thermodynamic and kinetic stability of nickel complexes. In particular, nickel may bind to a basolateral population of metal carriers and block its own basolateral transfer in a concentration-dependent manner. Tight 63Ni binding to non-specific jejunal ligands is responsible for the unaltered high linear fraction of jejunal 63Ni load in iron-deficient and iron-adequate segments. Binding of 63Ni to food and tissue ligands in the small intestine may, thus, be a likely explanation for the low oral nickel toxicity.

Animals↗
PubMed2003

Duodenal mucosal reductase in wild-type and Hfe knockout mice on iron adequate, iron deficient, and iron rich feeding.

BACKGROUND: Genetic haemochromatosis is a common hereditary iron loading disorder in humans. The disease is associated with loss of function mutations in the HFE gene. This is thought to change iron stores via increased iron absorption. AIMS: In this study we investigated how adaptation of mucosal reductase activity is engaged in this process and how the changes compare with adaptation seen when an iron deficient diet is fed. METHODS: Duodenal mucosal surface reductase was measured with nitroblue tetrazolium in age matched groups of male Hfe knockout mice (Hfe) and wild- type mice fed a purified diet containing normal (iron adequate), high (iron rich), or low (iron deficient) iron concentrations. RESULTS: Reductase activity increased when mice were fed an iron deficient diet and decreased when they were fed an iron rich diet. Total villus activity, as measured by the average area under the activity curve along the crypt-villus axis, was increased 2.8-2.9-fold by iron deficiency in both genotypes. Approximately half of this difference was attributable to the significantly increased length of the villi in mice on an iron deficient diet (p<0.05). Hfe knockout did not affect villus length but increased mucosal reductase activity near the villus tips. Similar increases (1.3-1.6-fold) were seen on all diets but the increase was significant for iron deficient and iron loaded diets only (p<0.05). CONCLUSION: Hfe gene product and dietary iron downregulate villus reductase activity in mice.

Animals↗
PubMed2002

Hohenheim consensus workshop: copper.

Copper (Cu) is an essential trace element with many physiological functions. Homeostatic mechanisms exist to allow Cu to act as a cofactor in enzymatic processes and to prevent accumulation of Cu to toxic levels. The aim of this commentary is to better understand the role of dietary Cu supply in deficiency and under physiological and pathological conditions. The essentiality of Cu can be attributed to its role as a cofactor in a number of enzymes that are involved in the defence against oxidative stress. Cu, however, has a second face, that of a toxic compound as it is observed with accumulating evidence in hepatic, neurodegenerative and cardiovascular diseases. The destructive potential of Cu can be attributed to inherent physico-chemical properties. The main property is its ability to take part in Fenton-like reactions in which the highly reactive and extremely deleterious hydroxyl radical is formed. Diseases caused by dietary Cu overload could be based on a genetic predisposition. Thus, an assessment of risk-groups, such as infants with impaired mechanisms of Cu homeostasis regarding detoxification, is of special interest, as their Cu intake with resuspended formula milk may be very high. This implies the need for reliable diagnostic markers to determine the Cu status. These topics were introduced at the workshop by the participants followed by extensive group discussion. The consensus statements were agreed on by all members. One of the conclusions is that a re-assessment of published data is necessary and future research is required.

Cardiovascular Diseases↗
PubMed2002

Long-term sequelae of HFE deletion in C57BL/6 x 129/O1a mice, an animal model for hereditary haemochromatosis.

BACKGROUND: HFE knockout mice (C57BL/6 x 129/Ola strain) mimic the functional aberrations of human hereditary haemochromatosis (HH) in short-term experiments. The present study investigates functional and morphological long-term changes. METHODS: HFE(o/o), HFE(+/o) and HFE(+/+) mice were maintained on iron-rich and control diets for 2 weeks, 3, 12 and 18 months. Light microscopic tissue iron distribution, pathomorphological alterations, tissue iron content and oxidative stress were analysed in liver, pancreas, spleen, gastrointestinal tract, kidneys and myocardium. Additionally, duodenal 59Fe absorption and 59Fe whole body loss were measured. RESULTS: Iron distribution between organs and microscopic iron deposition in the tissues resembled the patterns described in HH. After 3 months of iron-rich feeding duodenal 59Fe absorption decreased to approximately 15% of iron-adequate controls but remained about twice as high in HFE(o/o) as in HFE(+/+) mice. Hepatic iron concentrations reached only half the values known to induce hepatic fibrosis in rats and humans, while whole body 59Fe loss was about twice as high. Consequently no hepatic fibrosis developed, although massive hepatocellular iron deposition and indication for oxidative stress were observed. CONCLUSION: C57BL/6 x 129/O1a HFE(o/o) mice mimic HH iron distribution and the regulation of intestinal iron absorption after long-term feeding. However, characteristic morphological late changes in untreated HH are not modelled.

Animals↗
PubMed2001

109Cd accumulation in the calcified parts of rat bones.

A recent epidemiological study showed an increased risk for bone fractures after chronic low-level cadmium exposure. This finding agrees with those of cadmium accumulation in rat bones after chronic oral exposure which reduced the mechanical strength of the bones. There are indications that ossicular cadmium uptake may be higher during growth and may contribute over proportion to life long cadmium accumulation in the skeleton. The present study investigates this hypothesis in 59 male Sprague-Dawley rats. 109Cd distribution showed no differences after intravenous (i.v.) administration of different doses (0.02-2.00 micromol 109Cd/kg body weight) and at different time points after injection (3 and 10 days). Iron-deficiency had no impact on 109Cd distribution, neither during growth nor in adult animals. Age, however, showed an impact on cadmium distribution. Hepatic 109Cd accumulation was significantly higher in adult rats while 109Cd distribution in the bones as well as 109Cd concentration in cortical and trabecular bone tissue was significantly higher during growth. No difference in 109Cd uptake was found between femur epiphysis and diaphysis after one-dose i.v. application, which is in contrast to earlier results after chronic oral cadmium administration to rats. This difference may be explained by a different saturation for cadmium uptake in these two bone sections. Cadmium exposure during growth, thus, seems to contribute considerably to cumulative ossicular cadmium accumulation over a lifetime and possibly to cadmium-derived bone fragility in advanced age.

Aging↗
PubMed2001

Safety aspects of iron in food.

During the last decades efforts regarding dietary iron supply focused mostly on the prevention of deficiencies, especially during growth and pregnancy. Correspondingly, homeostatic mechanisms increase intestinal iron absorption in iron deficiency, but its downregulation at high intake levels seems insufficient to prevent accumulation of high iron stores at high intake. There is no regulated iron excretion in overload. Excess of pharmaceutical iron may cause toxicity and therapeutic doses may cause gastrointestinal side effects. Chronic iron excess, e.g. in primary and secondary hemochromatosis, may lead to hepatic fibrosis, diabetes mellitus and cardiac failure. Chronic intake of 50-100 mg Fe/day of highly bioavailable iron with home-brewed beer in sub-Saharan Africans lead to cirrhosis and diabetes. Applying a safety factor of 2 would lead to an upper safe level of 25-50 mg Fe/day for this endpoint of conventional iron toxicity. However, beyond this kind of damage iron is known to catalyze the generation of hydroxyl radicals from superoxide anions and to increase oxidative stress which, in turn, increases free iron concentration. This self-amplifying process may cause damage to lipid membranes and proteins, which relates radical generation and organ damage after ischemia-reperfusion events to available free iron in clinical and experimental settings. Correspondingly, epidemiological studies as well as observations in heterozygotes for hereditary hemochromatosis suggest that the risk of atherosclerosis and acute myocardial infarction is related to body iron stores, though there is conflicting epidemiological evidence as well. The most recent and best controlled studies, however, support the hypothesis that iron stores are related to cardiovascular risk. Iron-amplified oxidative stress may also increase DNA damage, oxidative activation of precancerogens and support tumor cell growth. This is supported by experimental, clinical and epidemiological observations. Due to these mechanisms high iron stores may present a health hazard. Though this has not been finally proven, available evidence strongly recommends not to increase iron intake beyond physiological requirements. To avoid iron deficiency symptoms, on the other hand, care must be taken to meet recommended daily intake.

Anemia, Iron-Deficiency↗
PubMed2000

Use of gamma-spectrometry for simultaneous determination of 210Pb, 73As, 109Cd, 203Hg and 59Fe distribution and excretion in rats at low doses.

gamma-Spectrometry permits the identification and quantification of different gamma-isotopes in the same aliquot. To estimate the sensitivity and discriminative power of a comparably small and inexpensive 8% germanium detector, we determined the detection limits for simultaneously applied 210Pb, 73As, 109Cd, 203Hg and 59Fe. The concentration of Fe and of each of the four potential environmental contaminants was determined in aliquots from all organs and tissues 10 days after simultaneous i.v. administration (2 micromol/kg body weight) to adult and growing iron-deficient and iron-adequate rats. Relating these values to the total size of each organ permitted to derive a whole body distribution pattern for all five isotopes in each individual animal. Cumulative renal and faecal excretion values were determined during the 10 day distribution period to calculate the half-lives for both excretory pathways for all five isotopes simultaneously. Distribution and excretion values corresponded well to literature data. Extrapolation of the results showed that the detector would be sensitive enough to discriminate and quantify the five metals at human dietary exposure levels. The results recommend to use gamma-spectrometry to investigate kinetic aspects of interactions between toxic and essential trace metals, because the method reduces the number of required animals drastically.

Animals↗
PubMed1999

Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism.

The puzzling linkage between genetic hemochromatosis and histocompatibility loci became even more so when the gene involved, HFE, was identified. Indeed, within the well defined, mainly peptide-binding, MHC class I family of molecules, HFE seems to perform an unusual yet essential function. As yet, our understanding of HFE function in iron homeostasis is only partial; an even more open question is its possible role in the immune system. To advance on both of these avenues, we report the deletion of HFE alpha1 and alpha2 putative ligand binding domains in vivo. HFE-deficient animals were analyzed for a comprehensive set of metabolic and immune parameters. Faithfully mimicking human hemochromatosis, mice homozygous for this deletion develop iron overload, characterized by a higher plasma iron content and a raised transferrin saturation as well as an elevated hepatic iron load. The primary defect could, indeed, be traced to an augmented duodenal iron absorption. In parallel, measurement of the gut mucosal iron content as well as iron regulatory proteins allows a more informed evaluation of various hypotheses regarding the precise role of HFE in iron homeostasis. Finally, an extensive phenotyping of primary and secondary lymphoid organs including the gut provides no compelling evidence for an obvious immune-linked function for HFE.

Animals↗
PubMed1999

Interactions between drugs and vitamins at advanced age.

Drug consumption increases at advanced age due to increased morbidity. At the same time the state of repletion is reduced for several vitamins. Physiological and kinetic alterations in the elderly are reviewed in order to analyse possible interrelations between these two phenomena. At high age the status of all vitamins is compromised by reduced food intake. Decreased active intestinal transport and an increased propensity for atrophic gastritis may reduce the absorption of vitamins A, B1, folate and B12. Decreased exposure to sunlight and reduced cutaneous synthesis impair the vitamin D status. Studies on the state of vitamin repletion in hospital patients indicate a specific response of vitamins A, B1, B6 and C to drug administration at advanced age. Reduced food intake in the elderly is further compromised by drugs that impair appetite and absorption. Anticonvulsives and other drugs that induce hepatic microsomal enzymes accelerate vitamin D metabolism and aggravate post-menopausal osteoporosis. Acid inhibiting agents increase achlorhydria and reduce vitamin B12 absorption. Renal clearance of acidic drugs such as acetylsalicylic acid and barbituric acid, which is impaired at high age, is further reduced by high doses of vitamin C. Vitamin B6 reduces the therapeutic effect of L-dopa. When recognised, the negative effects of drug-vitamin interactions can be compensated by adequate vitamin supplementation and by adaptation of drug dosing.

Aged↗
PubMed1999

Iron regulatory protein as an endogenous sensor of iron in rat intestinal mucosa. Possible implications for the regulation of iron absorption.

Duodenal enterocytes adjust intestinal iron absorption to the body's state of iron repletion. Here we tested how iron supply from the blood modulates the RNA-binding activity of iron regulatory proteins (IRP-1 and IRP-2) in immature duodenal rat enterocytes, and whether the modulation is compatible with the hypothesis that IRPs, in turn, may regulate the expression of iron transport proteins in maturating enterocytes during migration to the villus tips. Tissue uptake of parenterally applied 59Fe along the duodenal crypt-villus axis was compared to local IRP-1 and IRP-2 activity and to duodenal 59Fe transport capacity 12 h, 48 h, and 72 h after intravenous iron administration to iron-deficient rats. IRP-1 and IRP-2 activity was significantly increased in iron-deficiency. 59Fe administrated from the blood side was almost exclusively taken up by crypt enterocytes. Accordingly, the activity of IRP-1 decreased at this site 12 h after parenteral iron administration, but remained high at the villus tips. After 48 h the bulk of 59Fe containing enterocytes had migrated to the villus tips. Correspondingly, IRP-1 activity was decreased at duodenal villus tips after 48 h. IRP-2 activity also tended to decrease, though the change was statistically not significant. IRP-2 activity remained significantly higher at duodenal villus tips than in crypts, even after 72 h. Intestinal iron absorption capacity decreased with the same delay as IRP-1 activity after intravenous iron administration. In the ileum 59Fe uptake from the blood and IRP activity showed no significant difference between crypt and villus region. Luminal administration of iron decreased duodenal IRP-1 and IRP-2 activity at tips and crypts within 2 h. Thus, recently absorbed iron becomes available to cytosolic IRP during its passage through the enterocyte. Our results are compatible with a role of IRPs in gearing the expression of intestinal iron transporters in the duodenal brushborder to the body's state of iron repletion.

Absorption↗
PubMed1999

Kinetic analysis of 59Fe movement across the intestinal wall in duodenal rat segments ex vivo.

Duodenal segments from iron-deficient and iron-adequate rats were luminally perfused ex vivo with solutions containing 1, 10, 50, 100, 200 and 500 micromol 59Fe/l. When duodenal tissue load and mucosal-to-serosal transport had reached a steady state, perfusion was continued without luminal 59Fe supply. Mobilization of 59Fe from the duodenal tissue into the serosally released absorbate followed first-order rate kinetics, which permitted calculation of the asymptotic maximum, the rate constant, and the initial mobilization rate for tissue-to-absorbate transfer. There was no evidence for adaptation of 59Fe tissue binding in iron-deficient segments. 59Fe tissue-to-absorbate transfer increased in proportion to the mobilizable fraction of recently absorbed iron in the tissue, which is indicative of simple diffusion or carrier-mediated transport below saturation. Regulation of the mucosal uptake step appears to determine the mobilizable 59Fe fraction and thus the adaptation of the overall iron absorption process to the demand. Iron retention in the duodenal tissue and iron transfer from here into the body appear not to be either regulated or rate limited.

Animals↗
PubMed1998

Iron supplementation.

Iron deficiency affects approx. 20% of the world population. Due to predominantly vegetarian diets that reduce the bioavailability of food iron drastically, deficiency states are most widely distributed in developing countries. In addition, iron demand is increased by blood losses and by fast growth which increases the risk of iron deficiency in infants, young adolescents, and in menstruating and pregnant women. The symptoms of iron deficiency include impaired physical and intellectual performance. Iron supplementation may help to break the vicious cycle between inadequate nutrition and poverty. Fortification programs have to consider social and health aspects, including provision against iron overload. Excess iron stores may promote cancer and increase the cardiovascular risk, though the latter is a subject of current debate. The best approach to control such risks is individual iron supplementation geared to the demand by adequate laboratory controls. However, this approach is too costly for general application in developing countries. Food-iron fortification has successfully reduced iron deficiency in many trials and, in comparison, is much cheaper. As iron deficiency is widely distributed in most developing countries, the risk of inducing iron overload in the general population is low. Genetically determined diseases that may lead to siderosis, such as hereditary haemochromatosis or thalassaemia major, show a limited geographic and ethnic distribution. Such subgroups can be largely avoided by targeting food-iron fortification to infants, young adolescents, or pregnant women. Food vehicle and iron compound have to be matched in order to optimise iron bioavailability and to avoid rancidity in food, spoiling its taste and odour. The fortification of salt, sugar and spice mixtures or of bakery products with a short shelf-life are valid approaches to this end. Alternatively, haem iron can be used to fortify cereal-based food staples in developing countries such as tortillas or chappaties. Thus, a variety of options is available to solve the technical problems of food iron fortification. However, optimal solutions have to be tailored to the individual situation in each country.

Anemia, Iron-Deficiency↗
PubMed1998

Pathobiochemical effects of graded magnesium deficiency in rats.

Severe Mg deficiency changed mineral homeostasis, induced membrane damage, increased lipid peroxidation and cytokine concentrations, and reduced immunocompetence. In order to investigate whether the pathobiochemical effects correlate directly with the degree of Mg deficiency or whether there might be a threshold with no detectable effects above, diets with 70, 110, 208, 330 and 850 ppm Mg were fed to growing Wistar rats. After feeding the diets for 0, 10, 20 and 30 days parameters of free radical action (malondialdehyde and vitamin E content), mineral content (Mg, Ca, Fe) in various tissues (liver, spleen, heart, kidney, muscle) and plasma parameters (Mg, Ca, Fe, alanine- and aspartate-aminotransferase) were measured. After 30 days 6-keto-prostaglandin F1 alpha, thromboxane B2, tumor necrosis factor-alpha, and immunoglobulins (IgG, IgM, IgA) were additionally analyzed. Tissue Mg content was either unchanged or only slightly reduced in severe Mg deficiency. Tissue Fe content rose when the extracellular Mg concentration was below 0.25 mM. There was a close positive correlation between tissue Fe and malondialdehyde content, and malondialdehyde was negatively correlated with vitamin E content. Below a threshold of about 0.25 mM plasma Mg concentration, transaminases increased in plasma. The same threshold could be observed for the increase of tissue Ca content, except in the kidney where calcifications were found already in mild Mg deficiency. Tumor necrosis factor-alpha and 6-keto-prostaglandin F1 alpha were increased when the plasma Mg concentration was below 0.15 mM, and thromboxane B2 was increased when plasma was lower than 0.25 mM. IgG and IgA were significantly reduced below 0.25 mM plasma Mg and IgM below 0.4 mM plasma Mg. Mild Mg deficiency, therefore, can be compensated and might not lead to pathological symptoms if not combined with other pathobiological conditions.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Kinetic analysis of the intestinal iron absorption process in situ. The potential of vascularly autoperfused intestinal loops.

1 Blood sampling from mesenteric venules during absorption in situ is a useful tool to analyse intestinal absorption kinetics and prehepatic metabolism in different sections of the rat small intestine. By use of a micromanipulator, the method can be applied to the duodenum. This part of the small intestine shows the strongest adaptation of non-haem iron absorption to the demand for iron. 2 Iron absorption kinetics was linear in duodenal and jejunal segments. In iron-deficient animals, intestinal iron absorption capacity was increased in the duodenum, while simultaneously determined galactose absorption showed no change. 3 In situ perfusion and cannulation of mesenteric venules in duodenal segments are described. The use of a micromanipulator permits varying the blood volume collected by changing the vertical angle between the cannula and the mesenteric vessel. 4 Intestinal iron absorption rates remained close to constant when blood flow rates were varied by a factor of about ten. Plasma concentrations of absorbed iron vs mesenteric blood flow rates followed a hyperbolic function, as the plasma concentration of absorbed iron in mesenteric venules increased to the same extent as the blood flow decreased. 5 As the plasma transferrin concentration did not change over the experimental period, the concentration of absorbed iron in the mesenteric plasma exceeded the iron-binding capacity of plasma transferrin at low blood flow rates. This observation shows that enhancement of intestinal iron absorption does not require a corresponding increase in plasma iron-binding capacity in the intestinal tissue. 6 Vascularly perfused gut loops were also used to measure prehepatic metabolism, which may influence organotropism of carcinogenic metabolites. Therefore, this type of preparation is likely to find a variety of toxicological applications.

Animals↗
PubMed1997

Bioavailability of oral vitamins, minerals, and trace elements in perspective.

Bioavailability of orally administered vitamins, minerals, and trace elements is subject to a complex set of influences. Still, administrative regulation is necessary on how to quantify it. The most common approach to this problem is to determine the fraction of an oral dose that reaches the systemic circulation. For micronutrients, however, this approach has to consider the physiological plasma concentration as well as the mechanisms that regulate intestinal absorption and distribution of micronutrients between functional and storage compartments in response to the demand. The rate of exchange between these compartments has an impact on the delivery of such compounds into the plasma compartment as well as on the plasma clearance. Monitoring the area under the plasma concentration time curve after oral administration is an inadequate tool for bioavailability determination if there are substantial impacts of homeostatic mechanisms on the plasma concentration of a micronutrient. In nutritional science the term "bioavailability" encompasses the sum of impacts that may reduce or foster the metabolic utilisation of a nutrient. Bioavailability in this sense can be quantified by the rate by which deficiency symptoms are cured or by the weight gain during growth. both of these endpoints, again, are influenced by homeostatic mechanisms. To exemplify the scope of impacts on parameters that are commonly used to quantify the bioavailability of oral micronutrient preparations the basic traits of homeostatic regulation are summarised and compared for iron, magnesium, vitamin A, folic acid, and vitamin B12. The mechanisms that adapt absorption, distribution, and excretion of these five micronutrients to the demand differ to such an extent that no common approach can be derived to consider these impacts in bioavailability determination. In consequence, therefore, we recommend to define and regulate individual strategies for bioavailability testing for each micronutrient with regulated kinetics.

Administration, Oral↗
PubMed1996

A modified device for the differentiated study of intestinal transfer in isolated intestinal segments from mice and suckling rats in vitro.

An increasing number of mice with genetic variation of intestinal transfer properties is becoming available. A luminal perfusion system for small intestinal segments, therefore, was adapted for the use in mice and rat pups to investigate longitudinal differences in intestinal drug and toxin transfer and to explore the adaptation of transfer properties during maturation under standardized conditions in vitro. At present, cell cultures are inadequate for this goal. The perfusator consists of an upper reservoir and a lower moist chamber to accommodate the intestinal segment. The luminal perfusion fluid is oxygenized and circulated by a gas lift. It is directed through the segment by two three-way taps. For safe and easy decontamination of radioactive substrates, the system is made entirely of glass. To perfuse fragile segments from small animals such as mice and rat pups in vitro, the perfusion pressure had to be reduced to 15 cm H2O column. Therefore, the design of the perfusator was changed, and the gas lift and the three-way taps were moved to the side. With segments from adult rats, the modified perfusor yielded the same transfer data for 59Fe, glucose, and water as did the standard device. Experiments with proximal and distal segments from mice and rat pups showed a longitudinal pattern of adaptation during maturation as well as due to iron deficiency that was in accordance with expectations extrapolated from literature.

Aging↗