ReviewCopper, oxidative stress, and human health
Introduction
The essentiality of copper (Cu) was established in 1928 when it was demonstrated that a deficit of Cu resulted in anemia in rodents (Hart et al., 1928). Cu deficiency is now recognized to be a common problem in many domesticated and wild animals, and marginal Cu deficiency is a problem in some human populations. Conversely, Cu toxicity, typically due to genetic disorders, can also be a significant health concern. Below, literature related to Cu deficiency and Cu toxicity is reviewed, with an emphasis on the role of Cu in oxidative defense mechanisms, and the consequences of Cu deficiency, and Cu toxicity, with respect to tissue oxidative stress. The idea that alterations in Cu metabolism may be involved in the pathogenesis of select diseases is also discussed. Due to space constraints, in many cases, review papers are cited in place of original literature. The interested reader is directed to these reviews for additional information. Finally, experimental animal models and cell culture models are primarily discussed as they relate to furthering our understanding of diseases and pathologies important to the human population.
Section snippets
Metabolic function and essentiality of copper
The essentiality of Cu for mammals was firmly established by Hart et al. who reported that Cu was required for erythropoeisis (Hart et al., 1928). Twenty years later, the essentiality of Cu for fetal development was established when it was shown that swayback, a neurodegenerative disorder with progressive myelopathy and ataxia in lambs, was due to a developmental Cu deficiency during pregnancy (Gambling and McArdle, 2004). The current US–Canadian Recommended Dietary Allowance (RDA) for Cu is 9
Copper and the oxidant defense system
Under conditions of Cu deficiency, several components of the oxidant defense system can be compromised. Predictably, the activities of CuZn-SOD and ceruloplasmin are sensitive to tissue Cu as these enzymes require Cu as a catalytic cofactor. A deficiency of Cu can also decrease the activities of certain non-Cu containing enzymes of the oxidant defense system including catalase and selenium-dependent glutathione peroxidase (Se-GPx). Moreover, Cu deficiency can alter other reactive oxygen species
Copper deficiency, reactive oxygen species, and oxidative damage
Given the ability of Cu to produce excessive amounts of ROS, a number of Cu transporters and Cu chaperones have evolved to protect the cell by regulating the uptake, distribution, efflux and delivery of this redox active metal. However, as noted above, Cu deficiency directly, or indirectly, also affects components of the oxidant defense system, and as a result, increased ROS and oxidative damage to lipid, DNA and proteins can be demonstrated in whole animal and cell culture models of Cu
Diabetes
Aceruloplasminemic individuals often present with diabetes. It is currently thought that the diabetes is an adverse consequence of increased Fe accumulation in the pancreas due to the lack of ferroxidase activity in the tissue. Under conditions of experimental dietary Cu deficiency in humans, altered glucose metabolism has been noted in some, but not all studies (Institute of Medicine, 2002a). Abnormal glucose homeostasis is not a common characteristic of infants with Menkes’ disease, or humans
Copper deficiency and nitric oxide metabolism
Nitric oxide (NO) produced by endothelial NO synthase (eNOS) has multiple roles and contributes to the regulation of vascular tone. Evidence is mounting that altered NO metabolism can affect vasodilation by a decrease in NO production and/or diversion of NO to peroxynitrite as a result of increased superoxide anion concentrations, which decreases bioactive NO. It is known that superoxide anions can react rapidly with NO. The reaction rate for superoxide anions and NO is ∼7 × 109 M−1 s−1, which is
Copper toxicity
As is discussed above, a deficit of Cu can result in multiple pathologies, many of which can be linked in part to Cu deficiency-induced alterations in the oxidant defense system which ultimately result in excessive oxidative stress and tissue damage. Similar to Cu deficiency, Cu toxicity can result in significant oxidative stress and subsequent tissue damage. The oxidative stress associated with Cu toxicity is in part a consequence of its redox reactivity, e.g. the ability of free Cu or low
Acknowledgements
This work was supported by National Institutes of Health grants HD-26777 and DK35747 (UC Davis Clinical Nutrition Research Unit), and a gift from the International Copper Association.
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