Invited reviewRisks and benefits of copper in light of new insights of copper homeostasis
Introduction
Copper is an essential micronutrient that forms part of several proteins involved in a variety of biological processes indispensable to sustain life [1], [2], [3], [4], [5], [6]. At the same time, it can be toxic when present in excess, the most noticeable chronic effect being liver damage. Nutritional recommendations for specific subgroups at risk of suffering adverse effects from moderate copper deficiency or excess is a challenge that requires better knowledge of relevant early changes associated with high and low copper intakes. Essentiality and toxicity of copper are well characterized by two rare genetic conditions: Menkes disease and Wilson disease. The former results in severe deficiency [7], [8], [9], with the primary outcome usually being death, while the latter results in severe liver damage (cirrhosis) due to copper induced oxidative damage in liver and other tissues [10], [11], [12]. However, when the degree of deficiency or copper excess is not so intense the effects are unclear; a major reason for this is that available copper indicators are not sensitive and specific to detect early changes [13], [14], [15].
During the last two decades there has been concern among investigators and health regulators for the possibility that the exposure to the customary amounts of copper encountered in daily life (mainly from drinking water and food) may represent health risk for special groups in the population, especially for children [16] and individuals that are heterozygotes for the mutated ATPase, copper transporting, beta polypeptide (ATP7B), also known as Wilsons disease protein (estimated at 1:90) [17]. Though the effects that copper deficiency has on the population can be important, up to date this situation is not well characterized. In this paper we will review relevant aspects of whole body copper metabolism, cell and molecular basis for copper homeostasis. We will also discuss the evidence available on adverse effects derived from copper deficiency and copper excess, the need for biomarkers that help defining the early adverse effects of high and low copper on human health. Finally, we will review the evidence supporting current dietary recommendations including upper safe limits of copper intake.
Section snippets
Copper homeostasis and metabolism
Copper is absorbed mainly in the duodenum, although it is thought that some absorption takes place in the stomach and in the distal part of the small intestine [18]. It is estimated that the efficiency of copper absorption in humans ranges between 12 and 60% [19] depending on copper intake, presence of dietary factors that may promote or inhibit its absorption and the copper status of the individual. As shown by studies using stable isotope techniques, the fractional absorption of copper
Copper intake from food
In humans, access to copper from the environment is limited. Food and drinking water and copper-containing supplements are the main sources of copper; acquisition of the metal through inhalation or dermal routes is negligible. Copper content in the diet varies widely because foodstuffs differ greatly in their natural copper content [52]. Factors such as season (copper concentration is higher in greener portions), soil quality, geography, water source and use of fertilizers influence the final
Copper deficiency
The idea of supplementing groups at risk for copper deficiency has been discussed for some time now during international venues. Potential beneficial effects of copper on bone health and cardiovascular disease are currently being investigated [65], [66], [67]. If these effects are confirmed, supplementing copper to vulnerable groups is an attractive strategy that deserves further evaluation. Nevertheless, studies will be required to assess how efficiently the biliary system will adapt to higher
Copper toxicity and adverse effects due to copper excess
Toxic effects associated with copper in individuals not suffering Wilson disease are rare. Acute toxicity has been widely described in individuals that by accident or with suicidal intention ingest large doses of copper. Depending on the copper dose, a lack of adequate and timely treatment may be fatal [83], [84], [85], [86], [87], [88]. At lower doses, early adverse responses after acute exposure to copper originate in the stomach and cause vagal stimulation, eliciting a reflex response of
Need for new biomarkers
The data discussed indicate that despite the wealth of knowledge gained in recent decades there is a clear need to improve our knowledge about early effects of both deficient copper intake and excess copper exposure. Copper status is tightly regulated, with potent mechanisms that downregulate intestinal copper absorption and upregulate biliary excretion within a rather wide range of exposure levels [31], [108]. As copper exposure or intake does not represent the body's ‘copper load’ at a given
Nutrient intake, requirements and recommendations
The concept of nutritional requirement has evolved over time. A nutritional requirement was defined by the World Health Organization, the Food and Agriculture Organization of the United Nations and the International Atomic Energy Agency (WHO/FAO/IAEA) Expert Consultation on Trace Elements in Human Nutrition and Health, as “the lowest continuing level of nutrient intake that, at a specified efficiency of utilisation, will maintain the defined level of nutriture in the individual” [124]. The
Risk assessment and safety considerations about copper intake
The basic premise of traditional trace element risk assessment is that it applies to toxic elements, which are not essential for life and have no function, such as lead. In these cases, reducing the recommended ingestion to zero represents the best option [136]. It is clear that this cannot be applied to essential minerals because both their deficiency and excess induce adverse health effects. To set an MRL for copper of 0.7 mg/d as done by SCF is an example of the dilemma posed by using the
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