Nickel is an essential trace mineral that is the cofactor for the urease enzyme (which hydrolyses the urea to the ammonia and the carbon dioxide in the gastric juice and in the soil bacteria) and that is increasingly recognised as an important regulator of the iron metabolism and of the nitrogen metabolism in humans. The nickel is present in the body in concentrations of approximately 0.1-0.5mg per 100g of tissue (with the highest concentrations in the bone, the liver, the kidney, and the pancreas), and it is obtained from the diet (particularly from the grains, the nuts, the legumes, the chocolate, and the drinking water) at typical intakes of 0.1-0.5mg daily. The nickel requirement in humans is very low (estimated at 25-35mcg daily), and the nickel deficiency has not been definitively described in humans (because the nickel intake from a typical diet is usually adequate to prevent the deficiency). However, the nickel deficiency has been well-characterised in ruminants (cattle, sheep, goats) — where it produces the reduced urease activity in the rumen, the impaired urea recycling, the abnormal iron metabolism, the hepatic iron accumulation, and the microcytic anaemia that are the hallmark of the nickel deficiency in these species. These findings in ruminants suggest that the nickel deficiency in humans may produce similar effects on the iron metabolism and on the urea excretion — and that the nickel supplementation may be beneficial in people with the iron deficiency anaemia and with the impaired urea excretion. The nickel is also a component of the nickel-titanium alloys that are used in the dental and the orthopaedic implants, and it can cause the allergic contact dermatitis in people who are sensitised to nickel — this nickel allergy is one of the most common causes of the contact dermatitis worldwide, affecting approximately 10-20% of the population.
Nickel and the Urease
The urease is the enzyme that hydrolyses the urea to the ammonia and the carbon dioxide — it is found in the gastric juice (where it is produced by the Helicobacter pylori bacteria and where it raises the gastric pH by generating the ammonia that neutralises the gastric acid, which is one of the mechanisms by which H. pylori survives in the acidic environment of the stomach), in the soil bacteria (where it is involved in the nitrogen cycle, converting the urea to the ammonia that is then used by the plants as a nitrogen source), and in the mammalian tissues (where its function is less well characterised but where it is thought to be involved in the urea cycle and in the nitrogen metabolism). The urease requires nickel as a cofactor — the nickel ion is located at the active site of the enzyme, where it coordinates the urea and facilitates its hydrolysis by stabilising the transition state. Without adequate nickel, the urease activity is reduced, the urea hydrolysis is impaired, and the urea accumulates in the blood (uraemia) — which is one of the primary manifestations of the nickel deficiency in ruminants and which may also occur in humans with the severe nickel deficiency.
The clinical importance of the nickel for the iron metabolism is underscored by the observation that the nickel deficiency in ruminants produces the abnormal iron metabolism, the hepatic iron accumulation, and the microcytic anaemia — all of which are the hallmark of the iron deficiency and which suggest that the nickel is required for the normal iron absorption, iron transport, or iron utilisation. The mechanism of this nickel-iron interaction is not yet characterised, but it may involve the nickel-dependent regulation of the iron absorption proteins (the divalent metal transporter 1, DMT1, in the duodenum and the ferroportin in the enterocytes and the macrophages) or the nickel-dependent regulation of the iron regulatory proteins (IRP1 and IRP2) that control the expression of the iron metabolism genes. These findings suggest that the nickel supplementation may be beneficial in people with the iron deficiency anaemia — particularly in people who do not respond to the iron supplementation alone and who may have a subclinical nickel deficiency that is contributing to their anaemia.
Practical Application
For general nickel supplementation, there is no established RDA or estimated average requirement for nickel in humans, because the nickel deficiency has not been definitively described in humans. The estimated safe and adequate intake is 25-35mcg daily for adults (from a typical diet that includes grains, nuts, legumes, and chocolate), and the tolerable upper intake level is 1mg daily for adults (above which the nickel can cause the dermatitis, the asthma, and the other symptoms of the nickel toxicity). For comprehensive iron and haematinic support, nickel pairs well with the iron (which is the primary haematinic and which is required for the haemoglobin synthesis — the combination of nickel and iron may be more effective than iron alone for some forms of iron deficiency anaemia), with the copper (which is required for the iron absorption and for the iron mobilisation from the liver — the nickel may enhance the copper-dependent iron metabolism), with the vitamin B6 (which is required for the haemoglobin synthesis and for the porphyrin synthesis), with the folate (which is required for the DNA synthesis in the rapidly dividing erythroid precursors in the bone marrow), and with the vitamin B12 (which is required for the DNA synthesis in the erythroid precursors and for the maturation of the red blood cells).
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