铜代谢异常相关疾病研究

铜是人类和动物重要的必需微量元素，参与体内蛋白质、氨基酸、核酸等营养物质的代谢，铜代谢异常会造成多种疾病。本文主要综述铜在糖尿病、动脉粥样硬化、冠心病、高脂血症、骨质疏松等的发生发展以及治疗方面的作用。     

冠心病人血液微量元素锰、铬、铜、锌的分析

本实验用电感耦合等离子体发射光谱仪测定了33名正常人和63名冠心病人,(急性心肌梗塞25人,陈旧性心肌梗塞29人,慢性冠心病患者9人)血液中微量元素Mn、Cr、Cu、Zn的含量。发现1.对照组血清Mn为0.02145±0.0107ppm;Cr为0.0230±0.0167ppm;Cu为0.905±0.278ppm;Zn为0.0230±0.404ppm;Cu/Zn比值为0.973±0.395。与冠心病组血清Mn、Cr无明显差异。2.不同发作天数的急性心肌梗塞患者血清Cu、Zn和Cu/Zn比值的动态比较,结果表明,在急性心肌梗塞发作时可出现一过性的血清Cu升高,Zn降低,Cu/Zn比值高于对照组,随时间推移铜锌比值逐渐下降。3.陈旧性心肌梗塞和慢性冠心病者血清Cu、Zn和Cu/Zn比值远较对照组低,Cu/Zn比值<0.6的百分比远较对照组多(P<0.01),说明Cu/Zn比值降低可能是冠心病易患因素。4.用Feisher判别法将血清铜锌比值和其它主要易患因素作了横向比较,证明铜锌比值下降是冠心病主要易患因素,并结合国内外资料作了初步探讨。     

Coronary heart disease: the zinc/copper hypothesis.

Epidemiologic and metabolic data are consanant with the hypothesis thata metabolic imbalance in regard to zinc and copper ia a major factor in the etiology of coronary heart disease. This metabolic imbalance is either a relative or an absoulte deficincey of copper characterized by a high ratio of zinc to copper. The imbalance results in hypercholesterolemia and increased mortaility die to coronary heart disease. The imbalance can occur due to the amounts of zince and copper in human food, to lack of protective substances in food or drinking water and to alterations in physiological status that produce adverse changes in the distribution of zinc and copper in certain important organs. Because no other agent, with the possible exception of cholesterol, has been related so closely to tisk, the ratio of zinc to copper may be the preponderant factor in the etiology of coronary heart disease.     

New developments in the regulation of intestinal copper absorption

The transition metal copper is an essential trace element involved in many enzymatic processes that require redox-chemistry. The redox-activity of copper is potentially harmful. Severe imbalance of copper homeostasis can occur with some hereditary disorders of copper metabolism. Copper is acquired from the diet by intestinal absorption and is subsequently distributed throughout the body. The regulation of intestinal copper absorption to maintain whole-body copper homeostasis is currently poorly understood. This review evaluates novel findings regarding the molecular mechanism of intestinal copper uptake. The role of recently identified transporters in enterocyte copper uptake and excretion into the portal circulation is described, and the regulation of dietary copper uptake during physiological and pathophysiological conditions is discussed.     

Serum copper concentration and coronary heart disease among US adults

Copper, a strong prooxidant, may play a role in atherogenesis. The author examined the association between serum copper concentration and mortality from coronary heart disease using data from the Second National Health and Nutrition Examination Survey (1976-1992). Serum copper concentration was determined using atomic absorption spectroscopy. After various exclusions, 151 deaths from coronary heart disease occurred among 4,574 participants aged > or =30 years. At baseline, the age-adjusted serum copper concentration was about 5% higher among participants who died from coronary heart disease than among those who did not (p = 0.072). After adjustment for age, sex, race, education, smoking status, systolic blood pressure, serum cholesterol, serum high density lipoprotein cholesterol, body mass index, recreational activity, nonrecreational activity, history of diabetes, and white blood cell count, the hazard ratios for death from coronary heart disease for serum copper concentrations in the second, third, and fourth quartiles (versus the first quartile) were 1.84 (95% confidence interval (CI): 0.93, 3.66), 2.14 (95% CI: 1.21, 3.77), and 2.87 (95% CI: 1.57, 5.25), respectively. Several prospective studies, including the present analysis, have found elevated serum copper concentrations to be associated with cardiovascular disease. Whether copper directly affects atherogenesis or is a marker of inflammation associated with atherosclerosis remains to be established.     

心脏病患者血清铜、锌、锰、铬、硒含量测定的临床意义

作者应用原子吸收光谱法和原子荧光光谱法测定了人血清铜、锌、锰、铬、及全血硒。测定对象分正常对照(40例),冠心病(36例),风湿性心脏瓣膜病(27例),扩张型心肌病(34例)4组。结果表明,正常人平均血铜值1.227±0.213μg/ml,锌1.0±0.149μg/ml,铬8.945±5.464ng/ml,锰12.163±4.21ng/ml,硒0.0625±0.03μg/ml,与文献报道值接近。其余三组心脏病人血铜值(1.448μg/ml,1.740μg/ml、1.746μg/ml)均显著升高(P<<0.001),血锌在冠心病、风心病组降低(P<0.01),铬三组无变化,锰仅在风心病组降低(P<0.01),硒在冠心病组增高(P<0.05),在扩张型心肌病组则显著降低(P<0.0001)。急性心肌梗塞(13例),血铜升高,而锌降低;心衰时血铜显著升高。以上变化对三种心脏病及急性心肌梗塞的诊断与鉴別、判断心脏的功能可能有一定意义。特别是扩张型心肌病呈现出特异性血硒降低,可能是该病的致病因素之一。     

Wilson's disease and hemochromatosis

Wilson's disease (WD) and hereditary hemochromatosis (HH) are two inherited disorders with potentially devastating and life-threatening complications. Their eminent treatability makes diagnosis in adolescence or young adulthood critical. WD is the result of abnormal copper homeostasis, causing copper overload and end-organ damage. Chelation therapy can be highly efficacious in preventing manifestations of WD. HH is caused by inappropriate absorption of dietary iron, typically as the result of a specific mutation, C282Y, in the HFE gene. End-organ disease from iron accumulation is protean and includes progressive damage of the liver, pancreas, skin, heart, and pituitary. It is important to permit therapeutic phlebotomy to commence before the onset of complications.     

Maternal Zinc,Copper, and Selenium Intakes during Pregnancy and Congenital Heart Defects

The effects of zinc, copper, and selenium on human congenital heart defects (CHDs) remain unclear. This study aimed to investigate the associations of the maternal total, dietary, and supplemental intakes of zinc, copper, and selenium during pregnancy with CHDs. A hospital-based case-control study was performed, including 474 cases and 948 controls in Northwest China. Eligible participants waiting for delivery were interviewed to report their diets and characteristics in pregnancy. Mixed logistic regression was adopted to examine associations and interactions between maternal intakes and CHDs. Higher total intakes of zinc, selenium, zinc to copper ratio, and selenium to copper ratio during pregnancy were associated with lower risks of total CHDs and the subtypes, and the tests for trend were significant (all p < 0.05). The significantly inverse associations with CHDs were also observed for dietary intakes of zinc, selenium, zinc to copper ratio, selenium to copper ratio, and zinc and selenium supplements use during pregnancy and in the first trimester. Moreover, high zinc and high selenium, even with low or high copper, showed a significantly reduced risk of total CHDs. Efforts to promote zinc and selenium intakes during pregnancy need to be strengthened to reduce the incidence of CHDs in the Chinese population.     

ATP7A transgenic and nontransgenic mice are resistant to high copper exposure

The protein affected in Menkes disease, ATP7A, is a copper (Cu)-transporting P-type ATPase that plays an important role in Cu homeostasis, but the full extent of this role has not been defined at a systemic level. Transgenic mice that overexpress the human ATP7A from the chicken beta-actin composite promoter (CAG) were used to further investigate the physiological function of ATP7A. Overexpression of ATP7A in the mice caused disturbances in Cu homeostasis, with depletion of Cu in some tissues, especially the heart. To investigate the effect of overexpression of ATP7A when dietary Cu intake was markedly increased, normal and transgenic mice were exposed to drinking water containing 300 mg/L of Cu as Cu acetate for 3 mo. Cu exposure resulted in partial restoration of heart Cu concentrations in male transgenic mice. Despite the extended period of Cu exposure, Cu concentrations in the liver remained relatively unaffected, with a significant increase in male nontransgenic mice. Liver pathology was unremarkable except for small areas of fibrosis that were detected only in livers of the Cu-exposed transgenic mice. Intracellular localization of ATP7A in various tissues was not affected by Cu exposure. Plasma Cu concentration and ceruloplasmin oxidase activity were reduced in both Cu-exposed transgenic and nontransgenic mice. The expression levels of other candidate Cu homeostatic proteins, endogenous Atp7b, ceruloplasmin, Ctr1, and transgenic ATP7A were not altered significantly by Cu exposure. Overall, mice are remarkably resistant to high Cu loads and the overexpression of ATP7A has only moderate effects on the response to Cu exposure.     

Copper Levels in Cholestatic Infants on Parenteral Nutrition

Background: Copper levels are primarily regulated by biliary excretion. In cholestatic patients, there is a concern that the standard dose of copper in parenteral nutrition (PN) will result in excessive copper levels. This study looked retrospectively at cholestatic infants receiving PN with measured copper levels to ascertain if this is an actual clinical concern. Methods: All infants from the previous 10 years receiving PN who had a copper level checked and were cholestatic were reviewed. Children with metabolic or liver structural anomalies were excluded from the review. Of the 28 patients found, 26 had gastrointestinal disorders, and 82% of these infants were on the standard PN copper dose (20 µg/kg/d). Results: Only one elevated copper level was found in a child with congenital heart disease, but 13 low levels were found. A smaller number of follow‐up copper levels demonstrated that despite cholestasis, some patients require copper supplementation above standard recommendations. Conclusion: Cholestasis does not appear to impair copper excretion enough to result in elevated levels. In fact, infants with gastrointestinal disorders may require higher than standard dosing. Monitoring copper levels appears to be necessary to appropriately regulate copper dosing for cholestatic infants receiving PN.     

Altered copper status in adult men with cystic fibrosis

OBJECTIVES: To measure indices of copper status in adult men with cystic fibrosis (CF). A previous study in children showed changes in copper homeostasis compared to controls. This study was designed to investigate whether this observation persisted into adulthood. METHODS: This was a case-control age-matched study using seven men with CF and six healthy men. Blood samples were drawn into metal free tubes and fractionated into plasma, polymorphonuclear cells, mononuclear cells and erythrocytes. Cell fractions were assayed for copper and CuZn-superoxide dismutase; plasma was assayed for ceruloplasmin. RESULTS: The men with cystic fibrosis had significantly greater plasma copper and ceruloplasmin activity, yet had significantly lower copper-zinc superoxide dismutase activity in mononuclear and polymorphonuclear cells. Furthermore, the mononuclear cells of the cystic fibrosis subjects had about 45% percent less copper-zinc superoxide dismutase protein. Cellular copper levels were not statistically different between the two groups. A significant correlation was found between lung function and copper-zinc superoxide dismutase activity in the polymorphonuclear cells. Iron status was normal. CONCLUSIONS: The results indicate that individuals with cystic fibrosis have altered copper distribution compared to control individuals. Some aspects are characteristic of an inflammatory response; however, other measures suggest that copper homeostasis may be abnormal. It is not known whether the deviation in copper homeostasis in these individuals is a result of poor copper absorption, inadequate dietary intake, a result of their chronic inflammation or a direct effect due to the defect in ion transport caused by the disease. However, this research suggests that the severity of the disease and the activity of a copper dependent enzyme may be related. Further work will be necessary to determine the cause of the abnormal copper homeostasis and whether correcting it has any bearing on the course of the disease.     

锌、铜对大鼠血脂水平影响的研究

用雄性断乳ｗｉｓｔａｒ大鼠研究了不同水平锌、铜对大鼠血脂水平的影响。结果显示：绝对或相对铜缺乏均引起血清胆固醇、甘油三酯浓度升高；而绝对或相对锌缺乏则主要引起高密度脂蛋白胆固醇（ＨＤＬ－Ｃ）和ＨＤＬ＿２－Ｃ浓度下降。相关分析表明：血清锌与ＨＤＬ－Ｃ、ＨＤＬ＿２－Ｃ呈明显正相关；血清铜与血清胆固醇、甘油三酯呈显著负相关。病理检查显示：除对照组外，其它各组主动脉组织形态均发生不同程度的病理改变，尤以高锌低铜、高铜低锌及低锌低铜组为著。提示在保持适宜铜水平的前提下，补充适量的锌以提高血清ＨＤＬ－Ｃ水平，可预防或延缓高脂血症的发生。     

Quantitative genetic analysis of brain copper and zinc in BXD recombinant inbred mice

Abstract

Copper and zinc are trace nutrients essential for normal brain function, yet an excess of these elements can be toxic. It is important therefore that these metals be closely regulated. We recently conducted a quantitative trait loci (QTL) analysis to identify chromosomal regions in the mouse containing possible regulatory genes. The animals came from 15 strains of the BXD/Ty recombinant inbred (RI) strain panel and the brain regions analyzed were frontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. Several QTL were identified for copper and/or zinc, most notably on chromosomes 1, 8, 16 and 17. Genetic correlational analysis also revealed associations between these metals and dopamine, cocaine responses, saccharine preference, immune response and seizure susceptibility. Notably, the QTL on chromosome 17 is also associated with seizure susceptibility and contains the histocompatibility H2 complex. This work shows that regulation of zinc and copper is under polygenic influence and is intimately related to CNS function. Future work will reveal genes underlying the QTL and how they interact with other genes and the environment. More importantly, revelation of the genetic underpinnings of copper and zinc brain homeostasis will aid our understanding of neurological diseases that are related to copper and zinc imbalance.     

Copper-2 Ingestion,Plus Increased Meat Eating Leading to Increased Copper Absorption,Are Major Factors Behind the Current Epidemic of Alzheimer’s Disease

It has become clear that copper toxicity is playing a major role in Alzheimer’s disease; but why is the brain copper toxicity with cognition loss in Alzheimer’s disease so much different clinically than brain copper toxicity in Wilson’s disease, which results in a movement disorder? Furthermore, why is the inorganic copper of supplement pills and in drinking water so much more damaging to cognition than the organic copper in food? A recent paper, which shows that almost all food copper is copper-1, that is the copper-2 of foods reverts to the reduced copper-1 form at death or harvest, gives new insight into these questions. The body has an intestinal transport system for copper-1, Ctr1, which channels copper-1 through the liver and into safe channels. Ctr1 cannot absorb copper-2, and some copper-2 bypasses the liver, ends up in the blood quickly, and is toxic to cognition. Humans evolved to handle copper-1 safely, but not copper-2. Alzheimer’s is at least in part, a copper-2 toxicity disease, while Wilson’s is a general copper overload disease. In this review, we will show that the epidemiology of the Alzheimer’s epidemic occurring in developed, but not undeveloped countries, fits with the epidemiology of exposure to copper-2 ingestion leached from copper plumbing and from copper supplement pill ingestion. Increased meat eating in developed countries is also a factor, because it increases copper absorption, and thus over all copper exposure.     

Dietary supplementation with t-butylhydroquinone reduces cardiac hypertrophy and anemia associated with copper deficiency in rats

The effect of dietary supplementation with the antioxidant, t-butylhydroquinone (TBHQ), on some of the cardiovascular consequences of copper deficiency was investigated. Rats were fed copper-deficient (CuD) diet containing 0.3 μg Cu/g of diet that were either nonsupplemented or supplemented with TBHQ (supplied in the dietary safflower oil at a concentration of 0.02%). Control rats were fed copper adequate (CuA) diet containing >5.0 μg Cu/g (CuA) that also were either nonsupplemented or supplemented with TBHQ. After five weeks, rats consuming CuD diet supplemented with TBHQ exihibited plasma copper concentrations, ceruloplasmin activities, and liver and heart copper concentrations that were significantly (P<0.05) lower than those of rats consuming either nonsupplemented or TBHQ supplemented CuA diet, but no different from those of rats consiming nonsupplemented CuD diet. However, rats consuming CuD diet supplemented with TBHQ had significantly (P<0.05) higher growth, hemoglobin concentrations, hematocrits, and red blood cell qistribution widths but lower heart weights than rats consuming nonsupplemented CuD diet. TBHQ supplementation had no effect on these variables in rats fed CuA diet. Thus, while TBHQ did not improve copper status, it did ameliorate the growth reduction, anemia, and cardiac hypertrophy associated with copper deficiency. These findings indirectly support the contention that oxidative damage contributes to the pathophysiological consequences of copper deficiency.     

Contributions of Ernst L. Wynder to chronic disease control worldwide and to preventive medicine

Ernst L. Wynder is internationally known for his important discoveries in the field of human chronic disease causation, that is the underlying mechanisms, studied in various animal models, as a foundation for recommendations on the prevention of these diseases. These include coronary heart disease, and the main human cancers including cancer of the lung, caused by traditional smoking habits, and the nutritionally linked cancers, namely cancer of the breast, prostate, colon, pancreas, and urinary bladder. Much of this research was performed in a chronic disease prevention institution--created by Dr. Wynder--the American Health Foundation. There were outreach programs to educate people about proper lifestyles to secure disease prevention, including beginning health education in children.     

Beer mitigates some effects of copper deficiency in rats

Because of an epidemiologic association of decreased risk of death from ischemic heart disease with moderate use of alcoholic beverages, and because numerous abnormalities found in people with ischemic heart disease are also found in animals deficient in copper, rats were fed a diet deficient in copper and were given either beer or water to drink. Rats drinking beer lived nearly six times as long and had lower plasma cholesterol, less cardiac enlargement, and higher liver copper. Apparent absorption and biological half-life of oral radiocopper were increased by beer. The effects were not attributable to alcohol, chromium, or copper in beer. Beer intakes were similar to those of some people in the United States. Results may explain seasonal cycles in plasma cholesterol and may be germane to the epidemiology of ischemic heart disease because diets in the United States seem to be low in copper.     

Copper speciation in the gill microenvironment of carp (Cyprinus carpio) at various levels of pH

The fish gill microenvironment of Cyprinus carpio under stress of copper exposure was investigated. pH and other parameters including free copper activity, alkalinity, and inorganic and organic carbons in the surrounding water (inspired water) and in the gill microenvironment (expired water) were measured or calculated at various levels of pH and varying total copper concentrations. The chemical equilibrium calculation (from MINEQA2) and complexation modeling (mucus-copper) were coupled to calculate both species distribution. The results indicate that the pH in the fish gill microenvironment was different from that in the surrounding water with a balance point around 6.9. The secretion of both CO(2) and mucus was affected in both linear and nonlinear ways when the fish were exposed to elevated concentrations of copper. The complexation capacity of the gill mucus was characterized by a conditional stability constant (logk(Cu-mucus)) of 5.37 along with a complexation equivalent concentration (L(Cu-mucus)) of 0.96 mmol Cu/mg C. For both the fish microenvironment and the surrounding water, the dominant copper species shifted from Cu(2+) to CuCO(3)(0) and to Cu(OH)(2)(0) when the pH of the surrounding water changed from 6.12 to 8.11. The change in copper speciation in the gill microenvironment is smaller than that in the surrounding water due to the pH buffering capacity of the fish gills.     

Glutathione metabolism and its implications for health

Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.