Plasma Copper Concentrations Research Articles

The assessment of biological variation components of copper, zinc, and selenium

Twelve healthy volunteers (4 women and 8 men aged 23 to 45 years) were assessed for biological variation in copper, zinc, and selenium indices. Blood was drawn from these individuals once a week for 12 weeks and then once a month for a further 3 months. Over 12 weeks the mean plasma concentrations of copper, zinc, and selenium (measured by atomic absorption spectrometry), were 16 ± 2.9, 14.1 ± 1.5, and 1.28 ± 0.13 μmol/L, respectively. The intraindividual and interindividual coefficients of variation (estimated using analysis of variance (ANOVA) techniques) were 11 and 14% (zinc), 8 and 19% (copper), and 12 and 14% (selenium), respectively. The analytical goal for imprecision was achieved for all three micronutrients, i.e., it was less than one-half of the measured intraindividual variation. The indices of individuality for all three elements indicated that an individual's results as reference values are more useful than population-based data. The critical difference for significance between serial results is relatively smaller for copper (23%) and zinc (30%) than that for selenium (35%). The monthly mean concentrations of the three micronutrients over 6 months demonstrated no seasonal pattern.

Plasma and erythrocyte copper level as an indicator of disease activity during malignancy

Copper and zinc concentrations in erythrocytes, plasma and whole blood were determined in mice bearing spontaneous-, transplanted- and benezo[ a]pyrene-induced-tumour. The transplanted tumours studied were Sarcoma 180, Ehrlich carcinoma, and Dalton's lymphoma. Copper concentration in the malignant-tumour-bearing mice showed significant increases in erythrocytes and plasma, when compared with their normal controls. However, the zinc concentrations, although depressed in the different constituents of blood, were not significant enough to warrant any attention. Utilization of erythrocyte copper level as an additional marker of cancer activity is discussed.

Zinc Status and Interleukin-1 -Induced Alterations in Mineral Metabolism in Rats

Changes in zinc (Zn) metabolism and interleukin-1 beta (IL-1 beta) release occur as part of the physiological response to tissue injury and trauma. In the present study, the influence of Zn status on the response to continuous low-dose IL-1 beta administration was evaluated. Rats were fed 50 micrograms Zn/g (adequate zinc; AZn) or 5 micrograms Zn/g (marginal zinc; MZn) diets for 14 days. On day 15, rats were infused via osmotic minipumps, with IL-1 beta (2.3 ng/hr) or saline (control, C) and euthanized 1, 3, or 7 days later. In the AZn rats, IL-1 beta infusion resulted in increased plasma copper (Cu) concentrations and ceruloplasmin (Cp) activity, and decreased iron (Fe) concentrations throughout the 7d period. These effects were most pronounced on d1 and d3. A similar trend was observed in the MZn rats, but IL-1 beta-induced increases in plasma Cu and Cp activity were less than in the AZn fed rats. In MZn and AZn IL-1 beta infused rats, plasma Zn was decreased on Day 1, and Day 3, respectively, compared with their respective controls. AZn IL-1 beta-infused rats were characterized by high liver Fe, Zn, and metallothionein (MT) concentrations on Day 1; by Day 7, only MT concentrations remained elevated. Liver MnSOD activity was 13%-29% higher in both the AZn- and MZn-IL-1 beta-infused rats than their respective controls on Day 3 and Day 7, with most significant increase observed on Day 7. These data show that Zn status can influence the response to low-dose IL-1 beta; this influence of Zn should be considered when IL-1 beta is given therapeutically.

Toxicokinetics of copper in rainbow trout ( Oncorhynchus mykiss)

Rainbow trout ( Oncorhynchus mykiss) received 80 μg copper kg −1 body weight as an intravenous injection of copper sulfate. Copper levels were analyzed by atomic absorption spectrometry in plasma samples collected before and at regular times after the copper injection. Plasma copper concentration-time curves were analyzed according to standard pharmacokinetic compartmental procedures. A two-compartment model was adapted to derive toxicokinetic parameters, including a time-independent component to assess the basal plasma copper levels before the copper injection. The volume of the central compartment 43 ml kg −1 was similar to that reported for rainbow trout plasma. Steady-state distribution volume was estimated in 178 ml kg −1. Distribution and final elimination half-lives were 7.2 and 195.5 min, respectively. Steady-state distribution volume, the area under the curve, the copper clearance and the medium retention time calculated by the two-compartment model were similar to those estimated using non-compartmental equations. These toxicokinetic data suggest a rapid elimination of copper from the exchangeable pool. Thus, during long-term waterborne copper exposures, plasma copper concentration would achieve a steady-state situation after a few hours or days; further accumulation of copper would be related to the binding of copper to non-exchangeable ligands which would not have toxicological consequences. The large number of factors associated to the capability of the fish to offer and produce non-exchangeable binding sites would explain the variety of responses on copper accumulation described in the literature.

Interactive Effects of Dietary Copper and Water Copper Level on Growth, Water Intake, and Plasma and Liver Copper Concentrations of Poults

The interactive effects of dietary Cu and water Cu on poult growth, water intake, whole-blood hemoglobin (Hb), and plasma and liver Cu concentrations were investigated using 232 9-d-old toms. Poults were randomly assigned to two levels of dietary Cu [Basal (B) and B + 204 mg Cu/kg diet] and to four levels of water Cu (0, 51.5, 103, and 206 mg Cu/kg water) in a 2 × 4 factorial arrangement of treatments. Each treatment was replicated six times. All poults received tap water during Days 1 to 5 followed by the water Cu treatments during Days 6 to 10. Water intake was measured daily and gain and feed intake were determined on Days 5 and 10. Day 1 to 5 gain was reduced (P < .02) in poults fed supplemental dietary Cu. Day 1 to 5 feed intake and gain:feed and Day 6 to 10 gain, feed intake, gain:feed, and water intake were not affected (P > .10) by dietary Cu. Liver Cu concentration was increased (P < .01) in poults fed supplemental dietary Cu, but Hb and plasma Cu concentrations were not affected (P > .10) by dietary Cu level. Day 6 to 10 gain, feed intake, gain:feed, and daily water intake were decreased (quadratic effect, P < .01) in poults fed supplemental water Cu. Plasma Cu concentration was increased (linear effect, P < .04) in poults fed supplemental water Cu, but Hb concentration was not affected (P > .10) by water Cu. Liver Cu concentration was increased more in poults receiving both supplemental dietary Cu and water Cu than in poults receiving either Cu source alone (dietary Cu by water Cu quadratic, P < .10). Addition of 206 ppm supplemental Cu to the water decreased poult growth and water intake. Supplementation of feed and water with Cu increased liver Cu accumulation in poults, and the effect was greater when feed and water Cu were provided simultaneously.

Copper transport in the Nagase analbuminemic rat

The copper binding components of serum and potential importance of albumin to copper transport were investigated in adult Nagase analbuminemic and Sprague-Dawley rats of both sexes. There was a sex difference in total plasma copper concentrations, which were 60 and 130% higher than in the parent strain, in male and female Nagase rats, respectively. The higher levels of plasma copper were accounted for by two- and threefold increases in ceruloplasmin, as measured by p-phenylenediamine oxidase activity and copper by atomic absorption after gel chromatography. Other nonalbumin plasma proteins were also present in higher concentrations. Albumin concentrations were one-four-thousandth that of Sprague-Dawley rats, at 15 micrograms/ml (determined by rocket immunoelectrophoresis and comparative Western blotting). The tissue distribution and rate of uptake of intravenously injected 67 Cu(II) were unaffected by the lack of circulating albumin. 67Cu entered the liver of Nagase rats at least as rapidly as in the parent strain and reemerged in the blood on ceruloplasmin at an accelerated rate. The initial binding of 67Cu(II) to plasma components was primarily to transcuprein compared with albumin in the case of Sprague-Dawley rats. In the Nagase rats, the rest of the 67Cu bound primarily to nonalbumin proteins with about the same size as albumin; in Sprague-Dawley rats, it bound primarily to transcuprein. Limited analyses of tissue copper confirmed previous reports showing no striking differences from the parent strain. We conclude that albumin is not critical to the normal distribution and metabolism of copper and that it may serve more as a reservoir for excess plasma copper than as a specific conduit for the delivery of this element to hepatocytes or other cells.

The combined effect of high iron and zinc intake on copper status in rats

The interactions between copper, zinc, and iron intake in rats were investigated with regard to copper status. Weanling male rats were fed purified diets containing two levels of each of the three elements in a 2(3) factorial design. The added amounts of copper, zinc, and iron in the diets were 5, 12, and 35 mg/kg feed or were 10 times as high. After feeding on the experimental diets for 4 wk, the rats were killed and copper concentrations in plasma and organs measured. Plasma copper concentration was lowered by high zinc and iron intakes but this was seen only in the rats fed the normal-copper instead of the high-copper diets. In essence, the effects of zinc and iron were additive. Neither in rats fed the normal-copper diets nor in those fed the high-copper diets did extra iron or zinc intake alter copper concentrations in liver, spleen, kidney, and tibia.

Blood plasma concentrations of microelements in endurance trained volunteers during hypokinesia and chronic hyperhydration

The objective of this investigation was to determine the effect of a daily intake of fluid and salt supplementation (FSS) in preventing the development of changes in blood plasma concentrations of microelements that occur during prolonged restriction of muscular activity (hypokinesia). The studies were performed on 30 endurance trained male volunteers aged 23-26 yr with an average maximum oxygen uptake 64 mL/kg/min during 364 d of hypokinesia (HK). They were divided into three equal groups: Ten volunteers were placed continuously under an average of 10,000 running steps/d (control subjects), ten volunteers were subjected continuously to HK without the use of FSS (hypokinetic subjects), and ten volunteers were submitted continuously to HK and consumed daily FSS in very small divided doses (hyperhydrated subjects). For the simulation of the hypokinetic effect, the hypokinetic and hyperhydrated endurance trained male volunteers were kept continuously under an average of 3000 walking steps/d for 364 d. Prior to their exposure to HK, all volunteers were on an average of 10,000 running steps/p d. During the prehypokinetic period of 60 d and during the hypokinetic period of 364 d were determined the concentrations of calcium, magnesium, manganese, lead, iron, copper, tin, nickel, zinc, and cobalamine in blood plasma of endurance trained volunteers. During the hypokinetic period blood plasma concentrations of microelements decreased in hyperhydrated volunteers, whereas in hypokinetic volunteers increased significantly. The differences between the hyperhydrated and hypokinetic volunteers were significant with respect to their concentrations of microelements in blood plasma. It was concluded that chronic hyperhydration may be used to normalized blood plasma concentrations of microelements in endurance trained volunteers during prolonged restriction of muscular activity.

Ascorbic acid feeding of rats reduces copper absorption, causing impaired copper status and depressed biliary copper excretion.

The feeding of diets enriched with ascorbic acid (10 g/kg) to rats has previously been shown to lower plasma and liver copper concentrations. The present studies corroborate this. We hypothesized that ascorbic acid initially reduces copper absorption, this effect being masked later by the stimulatory effect on copper absorption of the impaired copper status. We also hypothesized that the impaired copper status as induced by ascorbic acid feeding is followed by a diminished biliary excretion of copper in an attempt to preserve copper homeostasis. Our hypotheses are supported by the present studies. Ascorbic acid feeding initially reduced apparent copper absorption, and in the course of the experiment this effect tended to turn over into a stimulatory effect. Copper deficiency, as induced by feeding a diet containing 1 mg Cu/kg instead of 5 mg Cu/kg, systematically increased copper absorption. Biliary excretion of copper in rats given ascorbic acid was unaffected initially but became depressed after prolonged ascorbic acid feeding. A similar time course was seen for fecal endogenous copper excretion that was calculated as the difference between true and apparent copper absorption. Copper deficiency systematically reduced biliary copper excretion and fecal endogenous copper loss.

Safety, efficacy, and effects on copper metabolism of intrareticularly placed selenium boluses in beef heifer calves

Summary Intrareticularly placed sustained-release selenium boluses were administered to 1 group of selenium-deficient heifer calves (n = 16), and a second group (n = 16) was left as nontreated controls. Age range for all calves was 83 to 156 days. These boluses release 3 mg of selenium each day, as sodium selenite. Measurements of blood selenium concentration, plasma copper concentration, hepatic copper concentration, and body weight were made over a 188-day study. The treated group of calves had significantly higher mean blood selenium concentration at posttreatment days 68 (P &lt; 0.0001), 112 (P &lt; 0.0001), and 188 (P &lt; 0.005) than did the control group. Mean blood selenium concentration in the treated calves was &gt; 0.10 μg/ml for 188 days. These boluses were observed to be clinically safe; signs of selenium toxicosis were not detected and untoward effects were not seen in the selenium-treated calves. There were no differences between control and treatment groups with respect to mean hepatic copper concentration or mean plasma copper concentration. There were no observed differences between the control and treatment groups with respect to weight gain during the study.

Platelet cytochrome c oxidase activity is an indicator of copper status in rats

Male weanling rats were fed diets containing 0.2, 1.0, 1.9, 3.0, 4.2 and 5.4 μg Cu/g for five weeks. Significant (P<0.05) reductions in ceruloplasmin amine oxidase activity, plasma copper concentration, erythrocyte superoxide dismutase activity, hepatic copper concentration and hepatic Cu,Zn-superoxide dismutase activity occurred in rats consuming diets containing 3.0 μg Cu/g and below. Thus, copper deficiency occurred when dietary copper concentrations were 3.0 μg/g and below. The response of platelet cytochrome c oxidase activity to dietary copper content was similar to the other indices of copper status in that significant reductions occurred when dietary copper was 3.0 μg/g and below. Furthermore, platelet cytochrome c oxidase activity was positively correlated with hepatic copper concentration (R 2=0.83) and hepatic Cu,Zn-superoxide dismutase activity (R 2=0.78). Also, inclusion of platelet cytochrome c oxidase activity with ceruloplasmin activity and erythrocyte superoxide dismutase activity improved the ability of these indices to predict liver copper concentration and liver Cu,Zn-superoxide dismutase activity. These findings indicate that platelet cytochrome c oxidase activity may be useful as an indictor of copper status, particularly in marginal status and when used with one or more other indices of copper status.

Dietary fructose vs glucose lowers copper solubility in the digesta in the small intestine of rats.

The hypothesis was tested that dietary fructose vs glucose lowers copper solubility in the digesta in the small intestine of rats, which in turn causes a decreased copper absorption. Male rats were fed adequate-copper (5 mg Cu/kg) diets containing either fructose or glucose (709.4 g monosaccharide/kg) for a period of 5 wk. Fructose vs glucose significantly lowered copper concentrations in plasma and the liver, but did not alter hepatic copper mass. Fructose feeding resulted in a significantly lesser intestinal solubility of copper as based on either a smaller soluble fraction of copper in the liquid phase of small intestinal contents or a lower copper concentration in the liquid phase. The latter fructose effect can be explained by the observed fructose-induced increase in volume of liquid phase of intestinal digesta. After administration of a restricted amount of diet extrinsically labeled with 64Cu, rats fed fructose also had significantly lower soluble 64Cu fraction in the digesta of the small intestine. Although this study shows that fructose lowered intestinal copper solubility, only a slight reduction of apparent copper absorption was observed. It is suggested that the fructose-induced lowering of copper status in part counteracted the fructose effect on copper absorption at the level of the intestinal lumen.

Iron and zinc status in rats with diet-induced marginal deficiency of vitamin A and/or copper

The hypothesis was tested that there are interactions of marginal copper and vitamin A deficiency regarding iron and zinc status. Copper restriction (1 vs 5 mg Cu/kg diet) significantly lowered copper concentrations in plasma and tissues of rats and reduced blood hemoglobin, hematocrit, and iron concentrations in tibia and femur, but raised iron concentrations in liver. Vitamin A restriction (0 vs 4000 IU vitamin A/kg diet) reduced plasma retinol concentrations and induced a fall of blood hemoglobin and hematocrit. Neither copper nor vitamin A restriction for up to 42 d affected feed intake and body wt gain. There were no interrelated effects of vitamin A and copper deficiency on iron status. Copper deficiency slightly depressed liver, spleen, and kidney zinc concentrations. Vitamin A deficiency lowered zinc concentrations in heart, but only when the diets were deficient in copper.

The release of vasoactive substances by cultured trophoblast cells in normal and preeclamptic pregnancies

The concentration of nutritionally important minerals in circulation is under tight homeostatic control, however, physical activity and aging influence their body stores and nutritional requirement. The aim of this study was to evaluate the effect of both physical activity and age on plasma concentrations of copper, zinc, iron, and magnesium.Stratified cluster sampling was used for selection of study participants (N = 360) belonging to three physical activity groups: sedentary, moderately active, and highly active on the basis of their physical activity levels as 1.53, 1.8, and 2.3, respectively. They were also divided into six different age groups (18–20, 21–25, 26–30, 31–35, 36–40, and 41–45 y). We assessed nutritional status by determining their body composition using bioelectrical impedance method and measuring intake levels. Fasting blood samples were taken to separate plasma for analysis of copper, zinc, magnesium, and iron.There was a major difference (P < 0.001) in the mean value of plasma copper, zinc, magnesium, and iron for the three activity groups. The plasma copper and iron concentrations were higher in the moderately active group (copper: 1.59 ± 0.05 mg/L, iron: 0.79 ± 0.22 mg/L) whereas zinc concentration was higher in the sedentary group (2.37 ± 0.29 mg/L). Both the highly and moderately active groups had higher plasma magnesium levels compared with the sedentary group. Plasma copper, zinc, magnesium, and iron levels also were influenced by age in a different pattern with respect to physical activity.Physical activity-related energy expenditure and age play a remarkable role in deciphering the plasma mineral levels in the healthy individuals.

Plasma zinc and copper in Paris area preschool children with growth impairment

Plasma zinc, copper, and parameters of growth were measured in a group of 116 French preschool children, 2-5 yr-old from low-income households. Participants were selected on the basis of Z-scores of weight for height (WHZ) and height for age (HAZ). Zinc and copper concentrations of children with growth impairment (GI), defined by a WHZ and/or HAZ < -1 Z-score, were compared to those of age, sex, and ethnic origin matched controls (WHZ and HAZ > -1 Z-score). Mean (+/- SD) plasma zinc concentration was 12.58 +/- 1.84 mumol/L in the GI group, and 13.27 +/- 1.98 mumol/L in the controls. The difference of the means of paired samples was 0.69 +/- 2.34, and by paired t-test the significance reached p = 0.028. This effect was primarily a result of the weight retarded group (WHZ < -1 Z-score, p < 0.009) and to the girls (p < 0.05). There were no significant differences in plasma copper concentrations between groups. These results suggest the presence of marginal zinc deficiency in French preschool children with low weight for height Z-scores.

Assessment of copper status: effect of age and gender on reference ranges in healthy adults

We measured major indices related to copper nutritional status in 55 men and 86 women between ages 20 and 83 years who were in apparent good health. Plasma copper concentrations and both immunoreactive and enzymatically measured ceruloplasmin were significantly higher in women than in men and were higher in women taking oral contraceptives. Plasma copper, immunoreactive ceruloplasmin, and cytochrome-c oxidase in platelets and mononucleated leukocytes tended to increase with age. The ratio of enzymatic to immunoreactive ceruloplasmin, erythrocyte superoxide dismutase, and 67Cu uptake by erythrocytes were not significantly affected by either age or gender. Thus, factors other than copper nutriture--such as age, gender, and hormone use--need to be considered when using many of these indicators to evaluate copper nutritional status.

Copper status in rats fed diets supplemented with either vitamin E, vitamin A, or beta-carotene.

Copper status was measured in rats fed copper-adequate, purified diets supplemented with either vitamin E (250 IU/kg), vitamin A (40,000 IU/kg), or beta-carotene (2 g/kg). It was hypothesized that the extra intake of the antioxidants would spare vitamin C resulting in a decreased copper status as shown previously after supplementation with vitamin C. A significant increase in plasma ascorbate concentration was observed after beta-carotene supplementation, but not after supplemental vitamin E or vitamin A. Extra intake of either beta-carotene or vitamin A slightly, but significantly, raised plasma copper concentrations. Beta-carotene also slightly raised liver copper concentration. Supplemental vitamin E had no effect on plasma and liver copper concentrations. It is concluded that the observed relatively small effects of supplemental vitamin A and beta-carotene on copper status in rats are not mediated by changes in plasma vitamin C concentration.

Factors associated with variation in plasma copper levels in preterm infants of very low birth weight

At 2-weekly intervals from age 4-14 weeks, the possible effects on plasma copper concentration of gestation, multiple birth, fractional weight change from birth (W/BW) and, up to 10 weeks, average daily total copper intake from birth were explored in 43 preterm infants of very low birth weight. There was no significant association between the logarithm of the plasma copper concentration (ln Cu) and multiple birth at any time and no significant association between ln Cu and gestation was found from 4-12 weeks. From age 4-10 weeks, there was a significant negative correlation between ln Cu and W/BW and at 4, 6 and 10 weeks there was also a significant negative correlation between ln Cu and copper intake. W/BW and copper intake were correlated throughout. At 14 weeks, ln Cu correlated positively with gestation and negatively with W/BW but, at this age, gestation and W/BW were correlated. The maximum total variation (R2) in ln Cu explained by its regression on gestation, multiple birth, W/BW and/or copper intake combined was only about 31% (at 10 weeks). The potential for copper depletion may be greater in rapidly growing infants.

High intensity physical exercise induced effects on plasma levels of copper and zinc.

Physical exercise leads to many metabolic, cardiovascular, and muscular changes in the body. The trace elements (TE) zinc and copper are directly involved, as enzymatic cofactors, in many of these processes, especially those related to nutrients metabolism, oxygen transport, and formation of usable energy. The effects of high-intensity physical exercise on plasma levels of CU2+ and Zn2+ in 19 subjects are investigated (9 males and 10 females). Plasma copper concentration decreases, and plasma zinc concentration increases, after exercise, in both sexes. After 30 min recovery, both TE concentration values shifts toward rest values in both sexes. These results only partially agree with literature data, probably because we used the treadmill exercise, which makes many muscles work, whereas other authors made their subjects perform a cycloergometer exercise. Physical exercise causes a marked redistribution of TE (copper and zinc) between body stores, bloodstream, and tissues. The condition of high metabolism may lead to a deficiency of TE, requiring supplementation in order to maintain high level performance.

Serum Ceruloplasmin, Plasma Copper Concentration and Copper to Ceruloplasmin Ratio in Cervical Carcinoma

Several studies have shown that plasma/serum copper and ceruloplasmin concentrations are increased in various carcinomas. We determined serum concentrations of ceruloplasmin and plasma copper concentration to evaluate the clinical usefulness of these tests in patients with cervical carcinomas. There was a significantly higher ceruloplasmin concentration in patients with cervical carcinoma compared to healthy controls. Plasma concentrations of copper were not significantly different in the two groups of subjects. The copper to ceruloplasmin ratio was lower in cancer patients than in control subjects. There was a significant increase in the serum concentrations of ceruloplasmin with increasing FIGO stage of cancer. Copper concentration in advanced tumours (FIGO stage 3) were significantly higher compared to control subjects or FIGO 1 and 2. Copper to ceruloplasmin ratio was lower in FIGO stage 2 and 3 patients compared to stage 1 or control subjects. Ceruloplasmin can also discriminate between large tumours which are inoperable and early cervical carcinomas better than copper or copper to ceruloplasmin ratio.