Andrew Taylor

The role of metals in neurodegenerative processes: aluminum, manganese, and zinc.

Until the last decade, little attention was given by the neuroscience community to the neurometabolism of metals. However, the neurobiology of heavy metals is now receiving growing interest, since it has been linked to major neurodegenerative diseases. In the present review some metals that could possibly be involved in neurodegeneration are discussed. Two of them, manganese and zinc, are essential metals while aluminum is non-essential. Aluminum has long been known as a neurotoxic agent. It is an etiopathogenic factor in diseases related to long-term dialysis treatment, and it has been controversially invoked as an aggravating factor or cofactor in Alzheimers disease as well as in other neurodegenerative diseases. Manganese exposure can play an important role in causing Parkinsonian disturbances, possibly enhancing physiological aging of the brain in conjunction with genetic predisposition. An increased environmental burden of manganese may have deleterious effects on more sensitive subgroups of the population, with sub-threshold neurodegeneration in the basal ganglia, generating a pre-Parkinsonian condition. In the case of zinc, there has as yet been no evidence that it is involved in the etiology of neurodegenerative diseases in humans. Zinc is redox-inactive and, as a result of efficient homeostatic control, does not accumulate in excess. However, adverse symptoms in humans are observed on inhalation of zinc fumes, or accidental ingestion of unusually large amounts of zinc. Also, high concentrations of zinc have been found to kill bacteria, viruses, and cultured cells. Some of the possible mechanisms for cell death are reviewed.

Determinants of serum copper, zinc and selenium in healthy subjects

Background: We have investigated the association between serum copper, zinc and selenium concentrations, dietary intake, and demographic characteristics, including individual coronary risk factors, in healthy subjects. Methods: Serum copper, zinc and selenium were measured by atomic absorption spectrometry in 189 healthy subjects. Serum glutathione peroxidase and caeruloplasmin were also determined for each subject. A previously validated food frequency questionnaire was used to estimate the dietary trace element intake. Results: Male subjects had significantly lower serum copper (P<0.001) and caeruloplasmin (P<0.001), and higher serum zinc (P<0.05) and zinc:copper ratio (P<0.001) than female subjects. Significant differences were observed in serum copper and caeruloplasmin concentrations (P<0.01) with age. Weak but significant associations between dietary trace elements and their serum concentrations were observed for zinc (r=0.18, P=0.02), copper (r=0.17, P=0.03) and selenium (r=0.19, P=0.02). Obese subjects had significantly lower serum concentrations of zinc (P<0.05). In multifactorial analysis, dietary zinc (P<0.05), serum high-density lipoprotein-cholesterol (HDL-C) (P<0.05), diastolic blood pressure (P<0.05) and age (P=0.05) emerged as major predictors of serum zinc concentrations. The corresponding predictors for serum copper were C-reactive protein (CRP) (P<0.001), serum HDL-C (P<0.001), gender (P=0.01), physical activity levels (P<0.05) and dietary copper (P<0.05). Serum selenium concentrations were predicted by serum total cholesterol (P<0.01), serum CRP concentrations (P<0.05) and dietary selenium (P<0.03). Conclusion: Serum copper, zinc and selenium concentrations are influenced by physiological conditions such as age, diet and gender. Their serum concentrations are also associated with coronary risk factors, including body mass index, levels of physical activity, serum HDL-C and CRP.

The possible role of copper ions in atherogenesis : the Blue Janus

It has been proposed that the oxidative modification of low density lipoprotein (LDL) is a key event in human atherogenesis. Copper ions can catalyse the oxidative modification of LDL in vitro and there is some evidence that they may also participate in the oxidation of LDL within the arterial wall. However, copper ions also form an intrinsic constituent of superoxide dismutase and caeruloplasmin, enzymes that may be involved in preventing oxidative injury. Atherosclerotic lesions frequently contain considerable quantities of extracellular matrix molecules. These may contribute to the expansion of the arterial neointima, causing luminal narrowing. They may also play a beneficial role by stabilising the plaque. Copper is an essential component of lysyl oxidase, an enzyme involved in the biosynthesis of collagen, which is a major constituent of the extracellular matrix. The impact of alterations in body copper status on atherogenesis is therefore difficult to predict. Experimental and epidemiological data are conflicting and therefore do not provide a clear resolution of this issue. We have reviewed the biochemical and cellular effects of copper ions that may play a role in atherogenesis.

Detection and monitoring of disorders of essential trace elements

Trace elements are defined simply as those elements which (individually) make up no more than 0·01% of the dry weight of the body. Some, like lead, are non-essential but others are required for normal health, function and development. Both essential and non-essential elements can be toxic if present in tissues and fluids in unusually large concentrations. Evidence to determine whether or not an element is truly essential is incomplete in some instances but Cotzias criteria for defining an element as essential are:

Fundamentals of analytical toxicology

The analytical toxicologist may be required to detect, identify, and in many cases measure a wide variety of compounds in samples from almost any part of the body or in related materials such as residues in syringes or in soil. This book gives principles and practical information on the analysis of drugs and poisons in biological specimens, particularly clinical and forensic specimens. After providing some background information the book covers aspects of sample collection, transport, storage and disposal, and sample preparation. Analytical techniques - colour tests and spectrophotometry, chromatography and electrophoresis, mass spectrometry, and immunoassay - are covered in depth, and a chapter is devoted to the analysis of trace elements and toxic metals. General aspects of method implementation/validation and laboratory operation are detailed, as is the role of the toxicology laboratory in validating and monitoring the performance of point of care testing (POCT) devices. The book concludes with reviews of xenobiotic absorption, distribution and metabolism, pharmacokinetics, and general aspects of the interpretation of analytical toxicology results. A clearly written, practical, integrated approach to the basics of analytical toxicology. Focuses on analytical, statistical and pharmacokinetic principles rather than detailed applications. Assumes only a basic knowledge of analytical chemistry. An accompanying website provides additional material and links to related sites. Written by an experienced team of authors,Fundamentals of Analytical Toxicology is an invaluable resource for those starting out in a career in analytical toxicology across a wide range of disciplines including clinical and forensic science, food safety, and pharmaceutical development.

Dietary copper supplementation reduces atherosclerosis in the cholesterol-fed rabbit

There has been considerable debate about how copper status may affect the biochemical and cellular processes associated with atherogenesis. In the present study we have attempted to address this issue directly by investigating the effects of dietary copper supplementation on processes likely to contribute to atherogenesis, using the cholesterol-fed New Zealand White rabbit model. Age matched rabbits (n = 16) were fed a 0.25-1% cholesterol diet to maintain plasma cholesterol concentrations at approximately 30 mmol/l. Eight of these animals also received 0.2% copper acetate. Control animals (n = 8) received rabbit chow without supplements. After 13 weeks on the experimental diets the animals were killed. Integrated cholesterol levels were similar for the cholesterol-fed animals (31.1+/-2.5 vs. 29.9+/-1.9 mmol/l weeks; P>0.05). Although integrated plasma copper levels were higher in the animals receiving the copper supplements, these did not differ significantly (19.0+/-4.8 vs. 15.1+/-2.9 micromol/l weeks; P>0.05). Tissue concentrations of copper were higher in the copper fed animals compared to those on cholesterol alone in aortic 14.0+/-0.75 vs. 1.8+/-0.2 microg/g wet tissue; P<0.05), carotid artery (11.4+/-3.5 vs. 4.9+/-0.9 microg/g wet tissue; P<0.05), and hepatic (332.5+/-28.6 vs. 3.3+/-1.1 microg/g wet tissue; P<0.0001) samples. The concentration of copper within the carotid artery was also significantly higher than that within the aorta (7.5+/-1.8 vs. 2.4+/-0.4 microg/g wet tissue; P<0.05). In animals fed a normal rabbit chow aortic, carotid and hepatic copper concentrations were 3.7+/-0.8, 9.4+/-3.4, and 5.0+/-1.6 microg/g, respectively. These values did not differ significantly from the cholesterol-fed animals (P>0.05). Plasma concentrations of caeruloplasmin, the major copper carrying protein, were estimated as plasma ferroxidase activity and were similar for the groups (P>0.05), as were aortic superoxide dismutase activity levels (P>0.05). Copper supplementation was associated with increased mononuclear cell adhesion to the endothelium of the carotid endothelium, with 2.6+/-0.3 adherent monocytes/1000 endothelial cells in the cholesterol plus copper-fed animals compared to 1.3+/-0.3 in the cholesterol-fed group (P = 0.0006), and 0.1+/-0.1 in the control animals (P<0.002). This may reflect the higher concentrations of copper found within the carotid artery. Histology of the thoracic aorta at the level of the third and sixth intercostal arteries, showed that copper supplementation was associated with significantly smaller intimal lesions (P<0.05 and P<0.01, respectively). These data suggest that copper supplements possibly inhibit the progression of atherogenesis.

Determination of Erythrocyte Fatty Acids by Capillary Gas Liquid Chromatography

A capillary gas liquid chromatography method was established for the routine determination of fatty acid profiles from washed erythrocyte membranes. Only the five major fatty acids found in erythrocytes (palmitic, stearic, oleic, linoleic and arachidonic acids) had acceptable precision (CVs <10·0%) for use in establishing quantitative differences between groups of individuals. Reference values were established for the relative amounts of these five fatty acids in adults. Significant alterations in the relative concentrations of oleic and arachidonic acids were found after storage at +4°C for 24 h, which has important implications in the study of changes in erythrocyte fatty acids in cancer and diabetes.

A phase 1 trial of intravenous 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) in patients with advanced solid tumours

Background4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) is a water-soluble mitochondrial toxin that binds to adenine nucleotide translocase in the inner mitochondrial membrane, thereby targeting cell proliferation. This phase 1 study investigated safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSAO as a daily 1-h infusion for 5xa0days a week for 2xa0weeks in every three. Pharmacodynamics of GSAO was evaluated by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and circulating markers of angiogenesis.MethodsPatients with advanced solid tumours received GSAO in a dose-escalation trial according to a standard ‘3xa0+xa03’ design that was guided by toxicity and, for the final dose escalation, by arsenic PK data.ResultsA total of 34 patients were treated with GSAO across 9 dose levels (1.3–44.0xa0mg/m2). Treatment was well tolerated with few adverse events. An additional three patients were enrolled at the 12.4xa0mg/m2 dose level following a DLT of derangement of liver function tests (grade 4). At the 44.0xa0mg/m2 dose level, two out of three patients had DLTs (reversible encephalopathy; paroxysmal atrial fibrillation).ConclusionsThe MTD of GSAO was 22.0xa0mg/m2/day. There was no biomarker evidence from DCE-MRI or circulating markers of angiogenesis of an anti-vascular effect of GSAO.

Association between indices of body mass and antibody titres to heat-shock protein-60, -65 and -70 in healthy Caucasians.

We have previously shown that antibody titres to several heat-shock proteins (Hsps) are elevated in dyslipidaemic patients and subjects with established vascular disease. Obesity is known to be associated with raised serum inflammatory markers suggesting a state of heightened immune activation. Hence, we have investigated the association between indices of obesity and several Hsp antibody titres in healthy subjects. Subjects (n=170) were recruited from among employees at the University of Surrey and the Royal Surrey County Hospital, Guildford, UK. Of these subjects, 35 were obese with a body mass index (BMI)⩾30u2009kg/m2 (19 male and 16 female subjects), 58 were overweight with 30>BMI⩾25u2009kg/m2 (36 male and 22 female subjects) and 77 were of a normal weight with BMI<25u2009kg/m2 (31 male and 46 female subjects). Overall, obese subjects had significantly higher plasma anti-Hsp-60 (P<0.001), anti-Hsp-65 (P<0.05) and anti-Hsp-70 (P<0.05) compared with overweight and normal weight subjects.

Measurement of Zinc in Clinical Samples

and serum specimens and either may be analysed. Thus, most investigations of zinc-associated clinical problems require analysis of specimens of plasma or serum. In certain situations it is appropriate to determine urinary excretion while whole blood, erythrocyte, leucocyte or hair concentrations are relevant to some studies.i- Typical concentrations of zinc in these specimens are shown in Table 2. A few workers have monitored the zinc concentrations of plasma fractions (e.g. zinc bound to albumin, transferrin, and amino acids), in attempts to develop more sensitive parameters of zinc status than the total serum zinc concentration. 7 However, this line of investigation has not proven helpful. Methods for plasma fractionation of zinc are complex, involving techniques such as electrophoresis and ultrafiltration, which require large volumes of sample and risk contamination errors. Results can be of academic interest but clinically useful markers of zinc status have not been identified. Analyses of tissues, foodstuffs Zinc is an essential trace element for animals and man. It is a cofactor for a large number of enzymes in virtually all metabolic pathways, is a component of transcription activation factorsthe zinc fingers, is involved in neurotransmitter function, immune activity and the action of hormones such as insulin. Thus, zinc is of major importance in physiology and biochemistry and, by implication, to the health of the individual. Deficiency of zinc is manifest by a variety of symptoms (Table 1) and though uncommon, excessive exposure will also cause morbidity.? No more than 1% of the total body zinc is present in the circulation with around four-fifths of this fraction contained in the red cells. Plasma, therefore, contains about 0·2% of the total body load of zinc most of which is bound to albumin with the remainder found in 1)(-2 macroglobulin and amino acid complexes. High concentrations of zinc are found in tissues where cell turnover is rapid, such as the liver, testes and intestinal mucosa. The major zinc reservoirs include muscle, bone, skin and hair, but zinc is not readily mobilized from these sites in times of deficiency. Zinc deficiency will develop if there is inadequate dietary intake or absorption, excessive loss or failure to meet an increased demand. Investigation of zinc nutritional status is appropriate when there are symptoms suggestive of perturbation of zinc metabolism (Table 1), in patients receiving total parenteral nutrition, artificial diets or other nutritional setbacks, and where there is occupational exposure.? Despite the very low proportion of total body zinc in the plasma and the influence of the acute phase response, total plasma zinc concentration is the most useful indicator of deficiency.I: Concentrations of zinc are similar in plasma