Nickel: the pathway in the body · Biomarker & Laboratory Analysis

Nickel is part of the pathway “Nickel”. This page shows the whole pathway; the station of Nickel is highlighted.

Where this laboratory value sits: Environmental nickel — food, water, air, skin. Nickel occurs in soils and plants and reaches the gut with food and drinking water. With dust in the air it reaches the lungs, and through contact with nickel-bearing metal the outermost layers of skin. Little is absorbed from food. Source 1

In brief

Nickel is a metal found in soils, plants and foods. In the body it is present as a divalent ion, binds to histidine and albumin and is excreted mainly by the kidney. It occupies places of iron and zinc in proteins.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Environmental nickel → Divalent nickel In aqueous solution nickel is present mainly as a divalent ion. In this form it resembles iron and other divalent metals. It thus uses their transporters. Source 1, 2↑ supplies As a divalent ion, nickel resembles iron and other metals; in this form it is absorbed by their transporters and bound to proteins. established physiology Source 1, 2
   ⚖ When the balance tips

   too much — If a lot of dissolved nickel is present, more of it is available to transporters and binding sites of other divalent metals.

   too little — If little dissolved nickel is present, for example because it is bound in food, hardly any is absorbed.

   established physiology · Source 2

2. Divalent nickel → Via iron transporters DMT1 The transporter DMT1 carries divalent iron into the gut cell. In doing so it also carries other divalent metals such as nickel. With little iron, more DMT1 is made. Source 3, 2↑ supplies DMT1 delivers nickel into the gut cell because the transporter does not strictly distinguish divalent iron from other divalent metals. established physiology Source 3, 2
   ⚖ When the balance tips

   too much — If there is a lot of nickel in the gut, it competes with iron at DMT1.

   too little — If little nickel is present, DMT1 carries mainly iron; if iron is scarce, more DMT1 is made and it also absorbs more nickel.

   observed in studies · Source 3, 2

3. Via iron transporters → Nickel in the blood · Albumin In the blood nickel binds to the amino acid histidine and to a site at the start of the albumin chain made of aspartate, alanine and histidine. This keeps it dissolved in the blood. Source 4, 1↑ supplies Albumin and histidine keep nickel dissolved in the blood and deliver it to the tissues; nickel bound to histidine is small enough to be filtered by the kidney. established physiology Source 4, 1
   ⚖ When the balance tips

   too much — If there is a lot of nickel in the blood, more albumin binding sites are occupied, where copper otherwise also binds, and the share of small histidine compounds rises.

   too little — If there is little nickel in the blood, it is mostly bound to albumin.

   established physiology · Source 4, 1

4. Nickel in the blood → Distribution in the body Through the blood nickel spreads into the tissues; it is found enriched in kidney, lung and skin, among others. It mostly stays there only briefly. Source 1, 5↑ supplies The blood distributes nickel to the tissues; it barely accumulates there permanently, however, and most of it quickly reaches the kidney. established physiology Source 1, 5
   ⚖ When the balance tips

   too much — After a larger intake, nickel in blood and tissues rises quickly and falls again within a few days.

   too little — If intake is low, nickel remains in the tissues only in small amounts.

   established physiology · Source 5

5. Distribution in the body → Excretion in urine Nickel that has reached the blood is excreted mainly by the kidney. The part that is not absorbed leaves the gut with the stool. This happens within a few days. Source 5, 1↓ depletes The kidney removes nickel from the blood promptly; the part that is not absorbed leaves the gut with the stool. established physiology Source 5, 1
   ⚖ When the balance tips

   too much — If a lot of nickel is absorbed, the amount in the urine rises quickly with it, because the kidney excretes it promptly.

   too little — If the kidneys filter more slowly, nickel stays in the blood longer.

   established physiology · Source 5, 1

6. Into the cell → Binding to histidine Nickel binds preferentially to nitrogen atoms, for example to the side chain of the amino acid histidine in proteins; sulfur groups of glutathione bind it as well. Bound glutathione is then less available. Source 1, 2↓ depletes Nickel occupies nitrogen atoms of histidine and sulfur groups of glutathione; bound glutathione is less available for the cell's other tasks. observed in studies Source 1, 2
   ⚖ When the balance tips

   too much — If a lot of nickel is bound, more glutathione is occupied; in cell studies reactive oxygen species then increase.

   too little — If little nickel is present, histidine and glutathione remain mostly free for their own tasks.

   observed in studies · Source 2

7. Binding to histidine → Iron binding sites In enzymes that carry iron or zinc at their centre, nickel can occupy that place. The enzyme then works differently than with its own metal. In cell studies the cell then responds as if oxygen were low. Source 2↓ depletes Nickel displaces iron or zinc from enzymes; in cell studies it thereby inhibits iron-dependent enzymes that control the cell's oxygen signals. observed in studies Source 2
   ⚖ When the balance tips

   too much — If nickel occupies many iron sites, the cell responds in experiments as if little oxygen were present, and reads the corresponding genes.

   too little — If little nickel is present, these enzymes carry their own metal and work as intended.

   observed in studies · Source 2

8. Into the cell → Binding to TLR4 Nickel ions bind to histidines of the receptor TLR4; two receptor molecules then join together and pass a signal into the cell. The mouse TLR4 lacks these histidines. Source 6↑ supplies Nickel links two TLR4 molecules via histidines that the human receptor carries and the mouse receptor does not; in cell studies the signal releases inflammatory messengers. observed in studies Source 6
   ⚖ When the balance tips

   too much — If a lot of nickel binds to TLR4, more receptor pairs form in cell studies, and more inflammatory messengers are released.

   too little — If little nickel is present, TLR4 mostly stays single and gives hardly any signal via this route.

   observed in studies · Source 6

9. Binding to TLR4 → Nickel as a hapten Nickel bound to the body's own proteins is seen by immune cells as an altered protein. A small substance acting in this way is called a hapten. This stimulates immune cells. Source 1, 6↑ supplies As a hapten, nickel makes the body's own proteins recognisable to immune cells; in some people the immune system then forms a memory for nickel. observed in studies Source 1, 6
   ⚖ When the balance tips

   too much — If a lot of nickel reaches the skin, more altered proteins form, and immune cells are stimulated more strongly.

   too little — If little nickel reaches the skin, hardly any altered proteins form, and immune cells are barely stimulated via this route.

   observed in studies · Source 1, 6

Further stations

• Environmental nickel — food, water, air, skin Nickel occurs in soils and plants and reaches the gut with food and drinking water. With dust in the air it reaches the lungs, and through contact with nickel-bearing metal the outermost layers of skin. Little is absorbed from food. Source 1↑ supplies Food and drinking water supply most of the nickel that enters the body; dust reaches the lungs, and skin contact mainly the outermost layers of skin. established physiology Source 1
  ⚖ When the balance tips

  too much — If more nickel arrives, more of it reaches the blood; in studies, a much larger share passes across with water on an empty stomach than with a meal.

  too little — If little nickel arrives, correspondingly little reaches the blood; whether humans need nickel for any task has not been settled.

  observed in studies · Source 5, 2

• Into the cell — via metal transporters Cells absorb divalent nickel through transport routes for iron and other metals; small amounts enter through calcium channels. There it binds to proteins. Source 2, 3↑ supplies Metal transporters and, to a small extent, calcium channels bring nickel into the cell interior, where it binds to proteins. established physiology Source 2, 3
  ⚖ When the balance tips

  too much — If there is a lot of nickel around the cell, more of it gets in in cell studies, and the cell binds it to proteins and glutathione.

  too little — If little nickel is present, the transporters carry mainly their usual metals.

  observed in studies · Source 2

Cofactors in this pathway

• Iron — Nickel uses the iron transporter DMT1 and can occupy the place of iron in enzymes; iron competes for it Source 3, 2In the ORY catalogue as a laboratory value: Eisen
• Histidine — Amino acid that binds nickel through its nitrogen atom and keeps it dissolved in blood; the kidney then filters it Source 1, 4In the ORY catalogue as a laboratory value: Histidin
• Albumin — Transport protein of the blood; binds nickel at a site near the start of its chain; copper also binds there Source 4
• Glutathione — Binds nickel inside the cell through its sulfur group and is then unavailable for other tasks Source 1, 2In the ORY catalogue as a laboratory value: Glutathion (GSH)
• Zinc — In proteins nickel can bind at sites that otherwise carry zinc at their centre Source 2In the ORY catalogue as a laboratory value: Zink

Sources

1. Genchi G, Carocci A, Lauria G et al. Nickel: Human Health and Environmental Toxicology. Int J Environ Res Public Health 2020 · PubMed 31973020
2. Denkhaus E, Salnikow K. Nickel essentiality, toxicity, and carcinogenicity. Crit Rev Oncol Hematol 2002 · PubMed 11923067
3. Gunshin H, Mackenzie B, Berger UV et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997 · PubMed 9242408
4. Laussac JP, Sarkar B. Characterization of the copper(II)- and nickel(II)-transport site of human serum albumin. Biochemistry 1984 · PubMed 6547847
5. Sunderman FW Jr, Hopfer SM, Sweeney KR et al. Nickel absorption and kinetics in human volunteers. Proc Soc Exp Biol Med 1989 · PubMed 2717626
6. Raghavan B, Martin SF, Esser PR et al. Metal allergens nickel and cobalt facilitate TLR4 homodimerization independently of MD2. EMBO Rep 2012 · PubMed 23059983

Whole pathway: Nickel

Related pathways

• Aluminium — into the cell
• Blei — Eisen, Glutathion (GSH)
• Cadmium — Eisen, Glutathion (GSH)
• Quecksilber — Glutathion (GSH), Zink

As of 2026-09-18. Draft, written by Claude to schema v2; sources checked in PubMed; expert approval pending
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