Substances & Homeopatic Remedies

Zincum metallicum

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The toxicity of the metals increases sharply in the order zinc, cadmium, mercury. The toxicity of zinc is low. In drinking water zinc can be detected by taste only when it reaches a concentration of 15 parts per million (ppm); water containing 40 parts per million zinc has a definite metallic taste. Vomiting is induced when the zinc content exceeds 800 parts per million. Cases of fatal poisoning have resulted through the ingestion of zinc chloride or sulfide, but these are rare. Both zinc and zinc salts are well tolerated by the human skin. Excessive inhalation of zinc compounds can cause such toxic manifestations as fever, excessive salivation, and a cough that may cause vomiting; but the effects are not permanent. Compared with those of zinc, the toxic hazards of cadmium are quite high. It is soluble in the organic acids found in food and forms salts that are converted into cadmium chloride by the gastric juices. Even small quantities can cause poisoning, with the symptoms of increased salivation, persistent vomiting, abdominal pain, and diarrhea. Fatal cases have been reported. Cadmium has its most serious effect as a respiratory poison: a number of fatalities have resulted from breathing the fumes or dusts that arise when cadmium is heated. Symptoms are difficult or laboured breathing, a severe cough, and violent gastrointestinal disturbance. Mercury and its compounds are highly toxic. They can be handled safely, but stringent precautions must be taken to prevent absorption by inhalation, by ingestion, and through the skin. The main result of acute poisoning is damage to kidneys. Numerous cases of poisoning through the industrial use of inorganic mercury compounds have been known. In the 19th century the use of mercuric nitrate in the hat industry to carrot, or lay, the felt caused tremors and a physical disturbance that gave rise to the phrase "as mad as a hatter" and consequently was banned. Organic compounds of mercury, most notably the compounds of the aryl and alkyl families, were once widely used, primarily as fungicides in seeds, paint, and paper. The toxicity of such compounds is different. The behaviour of aryl salts-as for example phenylmercuric acetate-in the body is similar to that of inorganic compounds. Both groups if ingested cause vomiting, colic, and diarrhea, and both are skin irritants. No fatal case of aryl salt poisoning has been reported; however, exposure to alkyl salts has caused a number of deaths. The main target seems to be the central nervous system, and alkyl salts are capable of penetrating brain cells. They are only slowly excreted. Concern has been expressed at an apparent buildup of mercury in tuna, swordfish, and salmon, and many countries have set limits on the amounts allowable in edible fish. The use of mercurial fungicides and pesticides and the discharge of mercury-containing wastes were prohibited in the United States in the early 1970s because they were found to cause such contamination.
Zinc deficiency (prophylaxis and treatment)æZinc supplements are indicated in the prevention and treatment of zinc deficiency, which may result from inadequate nutrition or intestinal malabsorption and other conditions that interfere with zinc utilization or increase zinc losses from the body, 96 but does not occur in healthy individuals receiving an adequate balanced diet. For prophylaxis of zinc deficiency, dietary improvement, rather than supplementation, is advisable. For treatment of zinc deficiency, supplementation is preferred. 107
Deficiency of zinc may lead to growth retardation, hypogonadism in males, anorexia (possibly due to changes in taste and smell), depressed mental function, dermatitis, impaired wound-healing, suppressed immune function, diarrhea, and abnormal vitamin A metabolism with impaired night vision. 6, 17, 18, 23, 53
Recommended intakes may be increased and/or supplementation may be necessary in the following conditions (based on documented zinc deficiency):
Alcoholism 6, 23, 24
Burns 5, 6, 18
Cirrhosis of the liver 6, 18, 23
Diabetes mellitus 6, 22
Eating disordersæanorexia nervosa, 25, 27 bulimia 27
Gastrectomy
Genetic disorders 5, 6 æacrodermatitis enteropathica, Down's syndrome, sickle cell anemia, 35 thalassemia
Hemodialysis 5, 37
Infantsæpremature 5, 6, 50
Infections, chronic, due to decreased immune responses 17, 18
Intestinal diseasesæceliac, 20 Crohn's, 5 diarrhea, 17, 21 sprue, 34 ulcerative colitis 5
Intestinal parasitism 5, 6
Malabsorption syndromes associated with pancreatic insufficiencyæpancreatic disease, cystic fibrosis 5, 38
Renal diseasesænephrotic syndrome, 5, 52  renal failure, 6 uremia 37
Short bowel syndrome 5, 6
Skin disordersæexfoliative dermatoses, psoriasis 5, 6
Stress, prolonged 51
Trauma, prolonged 18
Some unusual diets (e.g., reducing diets that drastically restrict food selection) may not supply minimum daily requirements of zinc. Supplementation may be necessary in patients receiving total parenteral nutrition (TPN) 33 or undergoing rapid weight loss or in those with malnutrition, because of inadequate dietary intake.
Recommended intakes for all vitamins and most minerals are increased during pregnancy. Many physicians recommend that pregnant women receive multivitamin and mineral supplements, especially those pregnant women who do not consume an adequate diet and those in high-risk categories (i.e., women carrying more than one fetus, heavy cigarette smokers, and alcohol and drug abusers). However, taking excessive amounts of multivitamin and mineral supplements may be harmful to the mother and/or fetus and should be avoided. 60
There is some evidence that low serum zinc levels may lead to complications of pregnancy 70, 71 or congenital malformations. 73
Recommended intakes for all vitamins and most minerals are increased during breast-feeding. 2
Recommended intakes may be increased by the following: Folic acid, 66, 87, 88 penicillamine, 6, 45, 77 iron supplements, 28, 29, 30, 31, 32 or thiazide diuretics. 82, 89
[Wilson's disease (treatment adjunct)] *æZinc supplements have been used along with a reduced copper diet in the treatment of Wilson's disease in patients who are unable to tolerate penicillamine. 7, 63, 64, 65, 66, 67

Unaccepted
A potential role for zinc in retarding the progression of age-related macular degeneration has not been proven. 61, 62 Zinc salts have not been found to be beneficial in the treatment of acute intermittent porphyria. 44

* Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Molecular weightæElemental zinc: 65.37 49
Zinc chloride: 136.3 68, 69
Zinc gluconate: 455.68 69
Zinc sulfate: 287.5 68

Mechanism of action/Effect:
Nutritional supplementæZinc is necessary for the proper functioning of over 200 metalloenzymes, including carbonic anhydrase, carboxypeptidase A, alcohol dehydrogenase, alkaline phosphatase, and RNA polymerase. 45, 47, 48 It is also required to maintain structure in nucleic acids, proteins, and cell membranes. 33, 44  Physiological functions that are zinc dependent include cell growth and division, 49 sexual maturation and reproduction, 45, 49 dark adaptation and night vision, 47, 49 wound-healing, 49 host immunity, 45, 49 taste acuity, 46, 49 and possibly olfactory acuity. 46
Copper absorption inhibitoræLarge doses of zinc inhibit the absorption of copper. 63, 75, 76

Absorption:
Approximately 20 to 30% of dietary zinc is absorbed, 6 primarily from the duodenum and ileum. 43, 96 The amount absorbed is dependent on the bioavailability from food. Zinc is the most bioavailable from red meat and oysters. Phytates may impair absorption by chelation and formation of insoluble complexes at an alkaline pH. 96
After absorption, zinc is bound in the intestine to the protein metallothionein. 43
Endogenous zinc can be reabsorbed in the ileum and colon, creating an enteropancreatic circulation of zinc. 41, 43, 78

Protein binding:
Zinc is 60% bound to albumin; 30 to 40% bound to alpha-2 macroglobulin or transferrin; and 1% bound to amino acids, primarily histidine and cysteine. 23

Storage
Zinc is stored primarily in red and white blood cells, but also in the muscle, bone, skin, kidney, liver, pancreas, retina, and prostate. 1, 6

Time to peak concentration:
Approximately 2 hours. 43

Elimination:
Primarily fecal (approximately 90%); to a lesser extent in the urine and in perspiration. 1, 6

Precautions to Consider

Pregnancy/Reproduction
PregnancyæProblems in humans have not been documented with intake of normal daily recommended amounts. However, adequate and well controlled studies in humans have not been done.
Studies have not been done in animals.
FDA Pregnancy Category C (parenteral zinc). 1

Breast-feeding
Problems in humans have not been documented with intake of normal daily recommended amounts.

Pediatrics

Problems in pediatrics have not been documented with intake of normal daily recommended amounts.
Zinc injection that contains benzyl alcohol as a preservative should not be used in newborn and immature infants. The use of benzyl alcohol in neonates has been associated with a fatal toxic syndrome consisting of metabolic acidosis and CNS, respiratory, circulatory, and renal function impairment.

Geriatrics

Problems in geriatrics have not been documented with intake of normal daily recommended amounts. The elderly may be at risk of zinc deficiency due to poor food selection, decreased intestinal absorption of zinc, or medications which may decrease absorption or increase urinary loss of zinc.

Nutritional supplementæZinc is necessary for the proper functioning of over 200 metalloenzymes, including carbonic anhydrase, carboxypeptidase A, alcohol dehydrogenase, alkaline phosphatase, and RNA polymerase. 45, 47, 48 It is also required to maintain structure in nucleic acids, proteins, and cell membranes. 33, 44  Physiological functions that are zinc dependent include cell growth and division, 49 sexual maturation and reproduction, 45, 49 dark adaptation and night vision, 47, 49 wound-healing, 49 host immunity, 45, 49 taste acuity, 46, 49 and possibly olfactory acuity. 46
Copper absorption inhibitoræLarge doses of zinc inhibit the absorption of copper. 63, 75, 76

Absorption:

Approximately 20 to 30% of dietary zinc is absorbed, 6 primarily from the duodenum and ileum. 43, 96 The amount absorbed is dependent on the bioavailability from food. Zinc is the most bioavailable from red meat and oysters. Phytates may impair absorption by chelation and formation of insoluble complexes at an alkaline pH. 96
After absorption, zinc is bound in the intestine to the protein metallothionein. 43
Endogenous zinc can be reabsorbed in the ileum and colon, creating an enteropancreatic circulation of zinc.

Zinc is stored primarily in red and white blood cells, but also in the muscle, bone, skin, kidney, liver, pancreas, retina, and prostate.

large doses of zinc may inhibit copper absorption in the intestine; zinc supplements should be taken at least 2 hours after the administration of copper supplements.
concurrent use of large amounts of fiber, phosphorus, or phytates with zinc supplements may reduce zinc absorption by formation of nonabsorbable complexes; foods containing fiber, phosphorus, or phytates should be taken at least 2 hours after zinc supplements.
large doses of iron supplements can inhibit the intestinal absorption of zinc; 28, 29, 30, 31, 32 this, at one time, was a problem in individuals taking commercial multivitamin-mineral preparations or infant formulas that had a high iron to zinc ratio 29, 31 ; however, most firms in the U.S. have reformulated their products; zinc supplements should be taken at least 2 hours after iron supplements.
zinc supplementation may induce copper deficiency or further decrease serum copper concentrations.

Clinical effects of overdose

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)ænot necessarily inclusive:Hypotension (dizziness or fainting) 55; jaundice (yellow eyes or skin) 55; pulmonary edema (chest pain or shortness of breath) 55; vomiting 55.

 The best sources of zinc include lean red meats, seafoods (especially herring and oysters), peas, and beans. 2, 3, 4 Zinc is found in whole-grains; however, large amounts of whole-grain foods have been found to reduce zinc absorption. 2, 5, 6, 8 Zinc has been reported to leach from galvanized cookware or storage containers in the presence of acidic foods, causing toxicity. 9 Foods stored in unlacquered tin containers may cause a decrease in zinc available for absorption.

TOXICOLOGY

A case of reversible cytopenias associated with excessive zinc supplementation
Julie A. Irving, Andre Mattman, Gillian Lockitch, Kevin Farrell and Louis D. Wadsworth
From the Department of Pathology and Laboratory Medicine (Irving, Mattman, Lockitch, Wadsworth) and the Division of Pediatric Neurology (Farrell), Children's and Women's Health Centre of British Columbia and the University of British Columbia, Vancouver, BC.

Abstract

ZINC IS A COMMON SUPPLEMENT AND IS WIDELY AVAILABLE as a standard component of many over-the-counter products. A number of reports have identified an association between excessive zinc intake and severe cytopenia. We report a case of zinc-induced copper deficiency in a young adult to illustrate this under-recognized cause of anemia and neutropenia.

Severe anemia and neutropenia were identified during the investigation of mild edema in a 19-year-old woman with Hallervorden–Spatz syndrome. This rare, untreatable condition is characterized by progressive motor and cognitive impairment due to massive iron deposition in the basal ganglia. The patient's seizure-like episodes had been treated for many years with carbamazepine (Tegretol, 1900 mg daily); valproate (Epival, 500 mg daily) had been added 10 months before presentation. Her daily diet, via gastrojejunal feeding tube, consisted of 1000 mL of Jevity (Abbott Laboratories Ltd., Montreal, Que.) and 375 mL of Nutren 1.5 (Nestlé Clinical Nutrition Company, Deerfield, Ill.). As well, for the last 5 years she had been receiving supplemental vitamin E, vitamin C, N-acetylcysteine, selenium, riboflavin and zinc (50 mg twice daily).
Borderline anemia had been detected in a routine complete blood count 1 year before this presentation (Table 1). Now she was markedly anemic (hemoglobin level 49 g/L) and had severe neutropenia (neutrophil count < 0.1  109/L). The peripheral blood film (Fig. 1) revealed macrocytic anemia, with basophilic stippling of the erythrocytes and a low reticulocyte count, both features of ineffective erythropoiesis; the few neutrophils present showed nuclear hypolobation (acquired Pelger–Huët anomaly). These features had not been present in the blood film a year earlier.
Bone marrow biopsy showed extensive cytoplasmic vacuolation of erythrocyte and leukocyte precursors, with almost no evidence of normal leukocyte maturation. The increased numbers of dysplastic erythrocyte precursors with perinuclear iron ("ringed sideroblasts," not visible in the figures) confirmed the diagnosis of sideroblastic anemia.
The differential diagnosis of sideroblastic anemia includes lead intoxication, treatment with medications such as isoniazid, pyridoxine (vitamin B6) deficiency, long-term alcohol ingestion and zinc toxicity. Further history-taking and laboratory tests, including measurement of the blood lead level and the activity of erythrocyte aspartate transaminase (normal activity indicates adequate pyridoxine status), excluded each of these possibilities except zinc toxicity. The blood levels of carbamazepine and valproate were within the therapeutic ranges.

The daily intake of zinc for the previous 5 years, calculated from the enteral feeds and supplementation, had been 121.25 mg, approximately 15 times the recommended dietary allowance (RDA)1 (Table 2). In addition, the daily intake of copper, 2 mg, was approximately twice the RDA1 (Table 2). Zinc toxicity was confirmed by the elevated serum zinc, low serum copper and low serum ceruloplasmin levels
Zinc therapy was stopped but valproate therapy continued. All hematologic and trace-metal parameters showed strong trends toward normal after 4 weeks and were normal after 8 months (Table 1).

Comments

Zinc supplementation is beneficial in the management of a number of conditions, including acute diarrhea,2 the common cold,3 acne4 and progressive myoclonic epilepsy.5 Its putative effect is the enhancement of immune function. Many over-the-counter (OTC) zinc-lozenge products are now available; in 1989, an estimated 16% of US citizens were taking zinc supplements orally.6

Copper-deficiency anemia secondary to zinc excess was first reported in 1977,7 and 18 cases have subsequently been reported.8,9,10,11,12,13,14,15,16 Most of these cases involved self-medication with OTC dietary supplements; the daily amount of zinc ranged from 29 mg for 7 months12 to 2000 mg for 3 months.16 The daily zinc intake of our patient was 100 to 120 mg for 5 years. Instructions on a bottle of OTC zinc lozenges recommend 5 to 20 mg every 2 hours during the onset of a cold, to a maximum of 50 mg daily.

Copper deficiency secondary to zinc excess arises from an indirect interaction between the 2 metals in the intestine. When exposed to excess dietary zinc, the absorptive duodenal cells upregulate metallothionein, an intracellular metal-binding ligand.17 Metallothionein binds both zinc and copper ions but has a much greater affinity for copper. Dietary copper that is bound to metallothionein becomes sequestered within the duodenal enterocytes, which are sloughed into the intestinal lumen.18 Increased oral copper intake is ineffective in restoring the zinc–copper balance in the presence of excess dietary zinc, as the induced metallothionein continues to intercept the copper and reduce its absorption. This explains why our patient, despite taking twice the RDA of copper, became copper-deficient over time. Since ceruloplasmin, the main copper metalloprotein in the blood, is produced by the incorporation of cupric ions into a protein moiety, copper deficiency also results in reduced production and therefore a reduced serum concentration of ceruloplasmin.

In all the case reports, copper deficiency was associated with anemia. Bone marrow aspirates revealed vacuolation of erythroid and myeloid precursors, as well as ringed sideroblasts. Neutropenia with arrested granulocyte maturation has also been described.11,14 After zinc therapy was stopped, the hematologic indices reverted to normal in weeks to months.14

Possible contributing factors, such as prescription medications and underlying medical conditions, are important to consider in the differential diagnosis of sideroblastic anemia. In our patient, valproate therapy may have accounted for the severity of the abnormalities. In some studies, valproate has been associated with lower copper levels in serum or hair.19 Patients with Hallervorden–Spatz syndrome are thought to have altered iron metabolism only within the central nervous system. In our patient, the serum valproate levels were within the therapeutic range. Furthermore, the hematologic indices reverted to normal when the zinc therapy was stopped and the valproate and carbamazepine therapy continued at the previous dosages.

Excess zinc intake must be included in the differential diagnosis of sideroblastic anemia. Patients and caregivers may be unaware of zinc's potential toxicity when doses intended for short-term use are maintained long term. This lack of awareness is a particular concern with OTC remedies, which may be continued without input from a caregiver. In a patient with a history of excess zinc ingestion, the diagnosis of zinc-induced copper deficiency can be established from the decreased serum copper and ceruloplasmin levels along with the increased serum zinc level. All the hematologic effects are potentially reversible after the oral zinc therapy is stopped, although some patients require intravenous copper repletion.

As zinc supplementation is common, clinicians and pathologists should be alert to the serious hematologic effects of zinc-induced copper deficiency and recognize this condition as an avoidable and readily managed cause of anemia and neutropenia.



Drug Metab Pharmacokinet. 2002;17(4):340-7.  
Metallokinetic Study of Zinc in the Blood of Normal Rats Given Insulinomimetic Zinc(II) Complexes and Improvement of Diabetes Mellitus in Type 2 Diabetic GK Rats by their Oral Administration.
Fugono J, Fujimoto K, Yasui H, Kawabe K, Yoshikawa Y, Kojima Y, Sakurai H.
Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University.

In order to understand the insulinomimetic activity of zinc(II) complexes, we studied the metallokinetic features of zinc in the blood of normal rats given the zinc complexes, bis(maltolato)zinc(II) (Zn(mal)(2)) and bis(6-methylpicolinato)zinc(II) (Zn(6mpa)(2)) by comparing each of them with an ionic form of zinc chloride (ZnCl(2)). The bioavailability of the zinc(II) complexes following oral administration was enhanced to 1.4-1.5-fold that of ZnCl(2) with respect to zinc level. Based on the results of a metallokinetic analysis and administration method in normal rats, we examined the antidiabetic ability of the zinc(II) complexes in GK rats, a model animal of type 2 diabetes mellitus. High blood glucose levels of GK rats were normalized following intraperitoneal injections and oral administration of the zinc(II) complexes, in which the Zn(6mpa)(2) complex was found to be more effective than Zn(mal)(2). The present results are noteworthy, not only due to their potential relevance for clinical application, but also for the development of new zinc(II) complexes.

Toxicol Appl Pharmacol. 2004 Dec 1;201(2):149-55.  
Zinc might protect oxidative changes in the retina and pancreas at the early stage of diabetic rats.
Moustafa SA.
Department of Zoology, Faculty of Science, Suez Canal University, Ismailia, Egypt. Sohabdulla@hotmail.com

It is well documented that oxidative stress is a basic mechanism behind the development of diabetic retinopathy (DR). The current study was undertaken to elucidate the possible role of zinc as an antioxidant and a biological membrane stabilizer in the protection against (DR). Male Wistar rats weighing 250 +/- 50 g were made diabetic by injection with a single ip dose of alloxan (100 mg/kg). Another group of rats was simultaneously treated with alloxan (100 mg/kg) and a single ip dose of zinc chloride (ZnCl2) (5 mg/kg). Blood and tissue samples were collected at 24, 48, and 72 h post-treatment in both groups. Diabetic state was confirmed by the determination of plasma glucose levels (significantly elevated at any time of the experiment when compared with controls receiving vehicle). Plasma insulin was significantly increased 24 h after treatment in both alloxan and alloxan plus ZnCl2-treated groups, and then decreased markedly 48 and 72 h post treatment in both groups. Alloxan treatment depleted both retinal and liver glutathione contents. The decrease in retinal and liver GSH in alloxan-treated rats was accompanied with a sustained increase in their thiobarbituric acid (TBA) content. Simultaneous treatment of rats with alloxan and ZnCl2 blunted the sustained increment in plasma glucose induced by alloxan. The combined administration of alloxan and zinc reversed the depleting effect on retinal and hepatic GSH in alloxan-treated rats and reduced the elevations in TBA content of both retinas and livers. At variance with many other antioxidants the current results clearly indicate the beneficial effects of Zn in both controlling hyperglycemia and the protection of the retina against oxidative stress in diabetes which may help set a new direction toward the development of effective treatments of DR.



 J Cell Biochem. 2004 Oct 1;93(2):345-57. Related Articles, Links  
Zinc stabilizes adenomatous polyposis coli (APC) protein levels and induces cell cycle arrest in colon cancer cells.
Jaiswal AS, Narayan S.
Department of Anatomy and Cell Biology and UF Shands Cancer Center, College of Medicine, University of Florida, Gainesville, Florida 32610, USA.

In the present study, we investigated the mechanisms by which zinc causes growth arrest in colon cancer cells. The results suggest that zinc treatment stabilizes the levels of the wild-type adenomatous polyposis coli (APC) protein at the post-translational level since the APC mRNA levels and the promoter activity of the APC gene were decreased in HCT-116 cells (which express the wild-type APC gene) after treatment with ZnCl2. Increased levels of wild-type but not truncated APC proteins were required for the ZnCl2-mediated G2/M phase arrest in different colon cancer cell lines. We further tested whether serum-stimulation, which induces cell cycle arrest in the S phase, can relieve ZnCl2-induced G2/M phase arrest of HCT-116 cells. Results showed that in the HCT-116 cells pretreated with ZnCl2, the serum-stimulation neither changed the distribution of G2/M phase arrested cells nor the increased levels of APC protein. The G2/M phase arrest correlated with retarded growth of HCT-116 cells. To further establish that wild-type APC protein plays a role in ZnCl2-induced G2/M arrest, we treated SW480 colon cancer cells that express truncated APC protein. We found that ZnCl2 treatment did not induce G2/M phase arrest in SW480 cells; however, the cell growth was retarded due to the loss of E-cadherin and alpha-tubulin levels. These results suggest that ZnCl2 inhibits the proliferation of colon cancer cells (which carry the wild-type APC gene) through stabilization of the APC protein and cell cycle arrest in the G2/M phase. On the other hand, ZnCl2 inhibits the proliferation of colon cancer cells (which carry the mutant APC gene) by disrupting cellular attachment and microtubule stability. Copyright 2004 Wiley-Liss, Inc.

Biochemistry. 2004 Aug 10;43(31):9989-98. Related Articles, Links  
Zinc ions trigger conformational change and oligomerization of hepatitis B virus capsid protein.
Stray SJ, Ceres P, Zlotnick A.
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, Oklahoma 73190, USA.

Assembly of virus particles in infected cells is likely to be a tightly regulated process. Previously, we found that in vitro assembly of hepatitis B virus (HBV) capsid protein is highly dependent on protein and NaCl concentration. Here we show that micromolar concentrations of Zn2+ are sufficient to initiate assembly of capsid protein, whereas other mono- and divalent cations elicited assembly only at millimolar concentrations, similar to those required for NaCl-induced assembly. Altered intrinsic protein fluorescence and highly cooperative binding of at least four Zn2+ ions (KD approximately 7 microM) indicated that binding induced a conformational change in capsid protein. At 37 degrees C, Zn2+ enhanced the initial rate of assembly and produced normal capsids, but it did not alter the extent of assembly at equilibrium. Assembly mediated by high zinc concentrations (> or =300 microM) yielded few capsids but produced a population of oligomers recognized by capsid-specific antibodies, suggesting a kinetically trapped assembly reaction. Comparison of kinetic simulations to in vitro assembly reactions leads us to suggest that kinetic trapping was due to the enhancement of the nucleation rate relative to the elongation rate. Zinc-induced HBV assembly has hallmarks of an allosterically regulated process: ligand binding at one site influences binding at other sites (cooperativity) indicating that binding is associated with conformational change, and binding of ligand alters the biological activity of assembly. We conclude that zinc binding enhances the kinetics of assembly by promoting formation of an intermediate that is readily consumed in the reaction. Free zinc ions may not be the true in vivo activator of assembly, but they provide a model for regulation of assembly.

Cell Biol Int. 2004;28(6):423-31. Related Articles, Links  
Differences in intramembrane particle distribution in young and old human erythrocytes.
Cordero JF, Rodriguez PJ, Romero PJ.
Laboratory of Membrane Physiology, Institute of Experimental Biology, Faculty of Sciences, Central University of Venezuela, Aptdo. 47114, Caracas 1041-A, Venezuela.

The distribution of intramembrane particles in human erythrocytes was studied by freeze-fracture on young and old cells and compared to that obtained after ATP depletion or following addition of a clustering agent. It was shown that intramembrane particles became aggregated and the mean particle density increased as the cells aged. Likewise, both particle aggregation and increased density were found in young cells after moderate ATP depletion. In contrast, mean particle density was markedly reduced in both cell types after exhaustive depletion. Paradoxically, Zn treatment led to decreased particle density in young cells, whilst producing the opposite effect in aged cells. The results suggest that their low ATP content may account for the increased particle density of senescent cells.

Brain Res Bull. 2004 Apr 30;63(3):253-7.  
Release of amino acids by zinc in the hippocampus.
Takeda A, Minami A, Seki Y, Nakajima S, Oku N.
ìDepartment of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. takedaa@u-shizuoka-ken.ac.jp

Zinc exists in the synaptic vesicles of hippocampal mossy fibers in high concentrations. On the basis of inhibitory zinc action against glutamate release in the hippocampus, the role of zinc in release of several amino acids were studied in rat hippocampus by using in vivo microdialysis. When the hippocampal CA3 region was perfused with 10 microM ZnCl(2), the concentrations of glutamine, serine, arginine, aspartate, and glycine in the perfusate were significantly increased, whereas the concentrations of amino acids except for glycine were not increased by perfusion with 30 microM ZnCl(2). Chelation of endogenous zinc with 50 microM CaEDTA significantly decreased the concentrations of amino acids in the perfusate except for glycine. In the CA1 region, on the other hand, the concentrations of these five amino acids were not increased by perfusion with 10 microM ZnCl(2) and the concentrations of glutamine and glycine were decreased significantly. The present study suggests that zinc enhances release of glutamine, serine, arginine, and aspartate in the CA3 region and attenuates release of glutamine and glycine in the CA1 region. Zinc seems to modulate glutamatergic synapses multifunctionally in the hippocampus, because glutamine, serine, aspartate, and glycine are involved in synaptic neurotransmission.