Introduction:
The importance of copper dates back to the Bronze Age, around 2,000 BC, when copper-tin alloys were used as bronze widely in Europe (1). Copper is an essential metal that is essential to health and metabolism. Copper is widely found in nature, and is normally found in the diet in a wide range of foods, like fish, nuts, and legumes (5)
Figure 1: The chemical element copper as seen on the periodic table (4)
Because copper is so common, the main sources of exposure to the general population come through food, beverages, and drinking water. In industry, the main source of copper exposure is through inhalation during mining, welding, or smelting operations (1). In the general population, exposure to elevated levels of copper is usually through metal leeching from copper plumbing or copper lined cookware (2). Excess copper can also be found in drinking water, which is another source of toxicity and can be dangerous to both people, and aquatic life (3).
Biotransformation:
Copper is absorbed through the gastrointestinal tract and then rapidly enters the bloodstream (1). Once it is absorbed it is transformed through the following pathways:
Figure 2: Biotransformation of Copper (7)
Out of an average 2mg/day intake of copper, about 25% is not absorbed and is excreted directly. Of the remaining 75%, 50% forms a metallothionein (MT) complex, which is a protein complex that is important for copper homeostasis, protects from oxidative stress, and buffers against toxicity. From there, the complex is also eventually excreted. Then almost 25% of copper is transported to the liver, and is either incorporated into ceruloplasmin or excreted in bold. Most of the copper in the liver is excreted in the bile, but less than 5% of the copper circulates in blood serum bound to ceruloplasmin and also as unbound free serum copper.
Toxicokinetics:
Approximately 55% to 75% of an oral dose of copper is absorbed from the gastrointestinal tract (1). Following absorption, copper is transported into the serum where it binds to a series of copper-binding proteins and small peptides, such as albumin, and amino acids (1). Copper is mainly stored in the liver, which is greater than 80% of stored copper in the body (1). The other main location of stored copper is in the brain. Within the cell, a majority of copper is complexed by glutathione, MT, and cytosolic copper chaperons, which work in conjunction with copper-ATPases to maintain copper homeostasis (8,9). The rest of the absorbed copper is complexed by copper-containing proteins, where the metal serves as a cofactor in enzymatic reactions (10). The major route of excretion for excess copper is via the feces, with very little copper excreted into the urine (1). The major route of excretion from the liver is from bile secretion (1). Bile secretion, enterohepatic recirculation, and intestinal reabsorption all help to maintain copper homeostasis (1).
Figure 3: Video on the metabolism and toxicokinetics of Copper
Mechanism of Action and Target Organs:
Because Copper has different, stable oxidation states, copper is involved in many redox reactions in vivo. One of the main reactions is shown below:
Figure 4: Copper being used to reduce dangerous oxygen radicals that could cause cell death (5).
Oxygen radicals are the product of oxidative phosphorylation and the electron transport chain. Because these radicals are produced as a byproduct of energy production, they are unavoidable, and without enough copper present to transform those radicals, they could build up and cause cell damage and cell death. This is just one of the many uses for copper in vivo.
The main target organs for Copper include:
- Central Nervous System (CNS)
- Liver
- Kidneys
- Blood
- Skin
- Immune System
Symptoms of Toxicity and Treatment:
Figure 5: Symptoms and treatment of copper poisoning
Genetic Susceptibility:
The two main genetic diseases associated with copper are Wilson disease and Menkes Disease.
Wilson Disease:
This is an autosomal recessive genetic disorder of copper metabolism characterized by the excessive accumulation of copper in liver, brain, kidneys, and cornea (1).
Figure 6: Video about Wilson disease
Treatment for Wilson disease any disease that causes excessive accumulation of copper includes copper chelators and supplementation with zinc salts (1).
Menkes Disease:
Menkes disease is a rare, sex-linked genetic disorder in copper metabolism that results in copper deficiency in male infants (1). It is characterized by peculiar hair, failure to thrive, severe mental retardation, neurological impairment, connective tissue dysfunction, and death usually by three to five years of age (1).
Figure 7: Video about Menkes Disease
Treatment with copper injections has been shown to help improve the outcomes in Menkes disease, if started within days after birth (1). However, most infants with Menkes die within the first decade of life regardless of treatment.
Essentiality and Deficiency:
Copper is vital to health, and essential in all of the metabolic pathways as outlined in the table below:
Figure 8: Table of essentiality of Copper: Copper dependent proteins are involved in all of the physiological roles as defined above (6)
From the table above, we can see that copper is involved in a variety of redox reactions that are vital too many biological processes. Because copper is so essential to all of these process, deficiencies of copper are dangerous and can have a big impact on the health of an individual. Copper deficiency can be a result of malnutrition, genetic diseases such as Menkes disease, an overconsumption of zinc, or an overdose of Molybdenum (1).
Summary:
- Copper is an essential element that is vital to our health
- However, copper levels need to be kept within a normal range, because both excessive copper levels, and copper deficiency can have toxic affects to the body
- Most Copper comes from our diet, but excessive copper can be ingested from copper pipes used in plumbing, copper-lined cookware, and from industrial sources from inhalation during various mining and welding work
- Genetic disorders such as Wilson disease and Menkes disease can also cause either excessive accumulation of copper (Wilson), or extreme copper deficiency that results in death (Menkes)
- Copper has different stable oxidation states, so it is widely used in vivo in different redox reactions.
- Without copper, these reactions are affected which is why Menkes disease is so deadly
- Accumulation of excess copper can cause copper to accumulate in the brain and in the liver, causing many different neurological symptoms and liver damage
- An excess of copper can be treated with copper chelators and supplementation of zinc salts
Resources:
- Tokar EJ, Boyd WA, Freedman JH, Waalkes MP. Toxic Effects of Metals. In: Klaassen CD. eds. Casarett and Doull’s Toxicology: The Basic Science of Poisons, Eighth Edition. McGraw-Hill; Accessed June 16, 2020.
- ATSDR Toxicological Profile for Copper (Update). Atlanta, GA: Agency for Toxic Substances and Disease Registry; 2004b:1–272.
- Handy RD Chronic effects of copper exposure versus endocrine toxicity: two sides of the same toxicological process. Comp Biochem Physiol Part A. 2003;135:25–38.
- [Photo of Copper Element Periodic Table] 2020. Retrieved from https://fineartamerica.com/featured/periodic-table-of-elements-copper-cu-serge-averbukh.html?product=adult-tshirt
- Nelson LS. Copper. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank’s Toxicologic Emergencies, 10e. McGraw-Hill; Accessed June 17, 2020.
- Uauy, Ricardo & Olivares, Manuel & González, Mauricio. (1998). Essentiality of copper in human. The American journal of clinical nutrition. 67. 952S-959S.
- [Photo of Copper Biotransformation] 2020. Retrieved from http://www.eurowilson.org/en/living/guide/pathway/index.phtm
- Harris, ED. Cellular copper transport and metabolism. Annu Rev Nutr. 2000;20:291–310
- Mercer, JF. The molecular basis of copper-transport diseases. Trends Mol Med. 2001;7:64–69
- Stern, BR. Essentiality and toxicity in copper health risk assessment: overview, update and regulatory considerations. J Toxicol Environ Health A. 2010;73:114–127.