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

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

Where this laboratory value sits: Environmental arsenic — drinking water and food. Inorganic arsenic occurs in soils and groundwater and enters the body through drinking water and food. In seafood, arsenic is present mainly in organic forms. No role in the human body is known. Source 1

In brief

Arsenic is a semi-metal found in soils, groundwater and foods. In the body inorganic arsenic is methylated by the enzyme AS3MT, and trivalent forms bind to sulfur groups of proteins. Methylation uses up SAM.

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 arsenic → Arsenate and arsenite Inorganic arsenic occurs as arsenate (pentavalent) or as arsenite (trivalent). Arsenate resembles phosphate in structure, while arsenite binds to sulfur groups. Both thus occupy places of the body's own substances. Source 1, 4↓ depletes Arsenate substitutes for phosphate, arsenite binds to sulfur groups. Both thus occupy places of phosphate or of the body's own thiols. established physiology Source 1, 4
   ⚖ When the balance tips

   too much — If a lot of arsenate is present, it is built into reactions in place of phosphate; the resulting arsenate esters break down quickly, and the cell gains less ATP.

   too little — If little arsenic is present, the cell's phosphate sites and sulfur groups remain largely unoccupied.

   established physiology · Source 1, 4

2. Arsenate and arsenite → Into the gut cell Transporters Arsenate enters cells through phosphate transport routes, arsenite through aquaglyceroporins — channels that also pass glycerol — and through sugar transporters. The transporters mistake it for their usual substances. Source 2↑ supplies Phosphate transporters, aquaglyceroporins and sugar transporters deliver arsenic into the cell because they mistake it for their usual substances. established physiology Source 2
   ⚖ When the balance tips

   too much — If there is a lot of arsenic in the gut, more of it enters through these transporters; phosphate competes with arsenate for the same route.

   too little — If little arsenic is present, the transporters carry almost only their usual substances.

   established physiology · Source 2

3. Into the gut cell → Arsenic in the blood From the gut wall arsenic reaches the blood and from there the liver and other tissues. Most of it is methylated in the liver. Source 1, 2↑ supplies The blood delivers arsenic mainly to the liver, where most of it is methylated; from there it spreads to other tissues. established physiology Source 1, 2
   ⚖ When the balance tips

   too much — If there is a lot of arsenic in the blood, more of it also reaches tissues outside the liver, such as skin and hair.

   too little — If there is little arsenic in the blood, it is mostly methylated in the liver and excreted by the kidney.

   established physiology · Source 1

4. Arsenic in the blood → Skin, hair, nails · Keratin Keratin, the protein of skin, hair and nails, holds many sulfur groups. Trivalent arsenic binds to them and stays bound there for a longer time. It grows out with them. Source 1, 4↓ depletes Keratin withdraws trivalent arsenic from the circulation and holds it in skin, hair and nails; it grows out with them. established physiology Source 1, 4
   ⚖ When the balance tips

   too much — If a lot of trivalent arsenic is in circulation, more is deposited in keratin; in hair and nails it remains until they have grown out.

   too little — If little is in circulation, hardly any is deposited, and newly growing hair contains little arsenic.

   established physiology · Source 1, 4

5. Arsenite in the cell → MMA(V) AS3MT · SAM The enzyme AS3MT transfers a methyl group from SAM onto arsenite, forming monomethylarsonic acid. It barely binds to sulfur groups. Source 3↓ depletes The first methylation uses up one methyl group from SAM. MMA(V) is pentavalent and barely binds to sulfur groups; it is reduced to the next stage or excreted. established physiology Source 3
   ⚖ When the balance tips

   too much — If a lot of MMA(V) accumulates, more glutathione is needed for the reduction and more SAM for the second methylation; part of it appears unchanged in the urine.

   too little — If little SAM is available, for example because folate or vitamin B12 is scarce, less MMA(V) forms, and more inorganic arsenic is left over.

   observed in studies · Source 3, 6

6. MMA(V) → MMA(III) · Glutathione Glutathione and related sulfur compounds reduce MMA(V) to the trivalent form MMA(III), which AS3MT can methylate a second time. In laboratory assays it binds enzymes more firmly than arsenite. Source 3, 1↓ depletes MMA(III) is an intermediate on the way to excretion and at the same time highly reactive: in laboratory assays it binds sulfur groups of enzymes such as the PDH complex more strongly than inorganic arsenite. observed in studies Source 3, 5
   ⚖ When the balance tips

   too much — If MMA(III) builds up because the second methylation cannot keep up, more of it stays bound to sulfur groups of enzymes.

   too little — If MMA(III) is quickly methylated further, little of it stays free, and the route leads promptly to excretion.

   observed in studies · Source 3, 5

7. MMA(III) → DMA(V) AS3MT · SAM A second methyl group from SAM leads to dimethylarsinic acid. It is the form that predominates in urine. It barely binds to sulfur groups. Source 3, 1↑ supplies The second methylation produces DMA(V), the form the kidney excretes most easily. It barely binds to sulfur groups and leaves the body mainly with the urine. established physiology Source 3, 1
   ⚖ When the balance tips

   too much — If a lot of DMA(V) forms, its share in the urine rises; methylation then runs through to the last stage.

   too little — If little DMA(V) forms, for example because SAM is scarce, more MMA and inorganic arsenic remain in the cells and in the urine.

   observed in studies · Source 1, 3, 6

8. DMA(V) → Excretion in urine Methylated forms leave the cell through transport proteins and are excreted by the kidney; part of them passes with bile into the gut. This is the main way arsenic leaves the body. Source 2↓ depletes Transport proteins and the kidney remove the methylated forms from cell and blood; part of them passes via the bile into the gut. established physiology Source 2
   ⚖ When the balance tips

   too much — If a lot of methylated arsenic is formed, the amount in the urine rises with it, because the kidney excretes these forms promptly.

   too little — If the kidneys filter more slowly, methylated forms stay in the blood longer.

   established physiology · Source 2, 1

9. Arsenite in the cell → Binding to thiols Trivalent arsenic binds with high preference to sulfur groups (thiols) of proteins and to glutathione; neighbouring thiols are held especially firmly. The occupied protein changes its shape. Source 4↓ depletes Trivalent arsenic occupies sulfur groups of proteins and glutathione; an occupied protein changes its shape, and its activity can change. established physiology Source 4
   ⚖ When the balance tips

   too much — If a lot of trivalent arsenic is present, more glutathione is bound, and more proteins with neighbouring sulfur groups are occupied.

   too little — If little is present, glutathione and the sulfur groups of proteins remain largely available for their own tasks.

   observed in studies · Source 4

10. Binding to thiols → Lipoic acid The lipoic acid of the pyruvate dehydrogenase complex carries two adjacent sulfur groups — exactly the arrangement that trivalent arsenic binds. It can then no longer accept an acetyl group. Source 5↓ depletes When trivalent arsenic binds to the two adjacent sulfur groups of lipoic acid, it can no longer accept an acetyl group in the PDH complex. observed in studies Source 5
    ⚖ When the balance tips

    too much — If a lot of lipoic acid is occupied, the PDH complex and the related alpha-ketoglutarate dehydrogenase complex work more slowly.

    too little — If little lipoic acid is occupied, both complexes run largely unaffected.

    observed in studies · Source 5

11. Pyruvate → Acetyl-CoA PDH complex · Lipoic acid The pyruvate dehydrogenase complex converts pyruvate into acetyl-CoA. While the lipoic acid is occupied by trivalent arsenic, this conversion runs more slowly. Less acetyl-CoA means less carbon for the citric acid cycle. Source 5↑ supplies Acetyl-CoA supplies carbon to the citric acid cycle; from it the cell gains most of its ATP in the mitochondria. established physiology Source 5
    ⚖ When the balance tips

    too much — If the PDH complex is free, plenty of acetyl-CoA forms, and the citric acid cycle receives its carbon from sugar.

    too little — If less acetyl-CoA forms because the lipoic acid is occupied, the citric acid cycle receives less carbon from sugar, and the cell makes less ATP.

    observed in studies · Source 5

Further stations

• Environmental arsenic — drinking water and food Inorganic arsenic occurs in soils and groundwater and enters the body through drinking water and food. In seafood, arsenic is present mainly in organic forms. No role in the human body is known. Source 1↑ supplies Drinking water and food supply inorganic arsenic; the organic forms from seafood, such as arsenobetaine, leave the body largely unchanged. established physiology Source 1
  ⚖ When the balance tips

  too much — If more inorganic arsenic arrives, more of it enters the cells, and the methylation route is used more heavily.

  too little — If little inorganic arsenic arrives, correspondingly little enters the cells; no role for arsenic in the human body is known.

  established physiology · Source 1

• Arsenite in the cell — trivalent form Inside the cell arsenic is mostly trivalent. Two routes lead on from here: methylation, and binding to sulfur groups of proteins. Methylation uses up SAM. Source 1, 3↓ depletes Trivalent arsenic is the starting point of both routes: AS3MT methylates it and uses up SAM in doing so, while the remainder occupies sulfur groups of proteins and glutathione. established physiology Source 1, 3
  ⚖ When the balance tips

  too much — If arsenite builds up in the cell, more SAM and glutathione are used up, and more of it binds to sulfur groups of proteins.

  too little — If there is little arsenite in the cell, it is mostly methylated, and only a little binds to proteins.

  observed in studies · Source 1, 3

• Pyruvate — end of glycolysis Pyruvate is formed when sugar is broken down in the cell. From it the PDH complex forms acetyl-CoA. Source 5↑ supplies Pyruvate supplies the carbon from which the PDH complex forms acetyl-CoA for the citric acid cycle. established physiology Source 5
  ⚖ When the balance tips

  too much — If the PDH complex cannot keep up, pyruvate builds up; more of it is then converted to lactate.

  too little — If little pyruvate is present, the PDH complex forms correspondingly little acetyl-CoA, whether or not arsenic is bound.

  observed in studies · Source 5

Cofactors in this pathway

• SAM (S-adenosylmethionine) — Methyl group donor of AS3MT, which methylates arsenite twice; with little SAM, more arsenic stays inorganic Source 3
• Glutathione — Reduces MMA(V) to MMA(III) and binds trivalent arsenic through its sulfur group; it is used up in the process Source 1, 3In the ORY catalogue as a laboratory value: Glutathion (GSH)
• Folate — Supplies methyl groups in one-carbon metabolism for the formation of SAM and thus for arsenic methylation Source 6In the ORY catalogue as a laboratory value: Folsäure
• Vitamin B12 — Cofactor of methionine synthase, which regenerates methionine for the formation of SAM Source 6In the ORY catalogue as a laboratory value: Vitamin B12
• Methionine — Amino acid from which, with ATP, the methyl group donor SAM is formed; without SAM, no methylation Source 6In the ORY catalogue as a laboratory value: Methionin
• Lipoic acid — Carries two adjacent sulfur groups in the pyruvate dehydrogenase complex; trivalent arsenic binds exactly there Source 5
• Selenium — Forms a joint compound with trivalent arsenic and glutathione that passes into bile Source 7In the ORY catalogue as a laboratory value: Selen

Sources

1. Watanabe T, Hirano S. Metabolism of arsenic and its toxicological relevance. Arch Toxicol 2013 · PubMed 22811022
2. Roggenbeck BA, Banerjee M, Leslie EM. Cellular arsenic transport pathways in mammals. J Environ Sci (China) 2016 · PubMed 28007179
3. Thomas DJ, Li J et al. Arsenic (+3 oxidation state) methyltransferase and the methylation of arsenicals. Exp Biol Med (Maywood) 2007 · PubMed 17202581
4. Shen S, Li XF et al. Arsenic binding to proteins. Chem Rev 2013 · PubMed 23808632
5. Bergquist ER, Fischer RJ et al. Inhibition by methylated organo-arsenicals of the respiratory 2-oxo-acid dehydrogenases. J Organomet Chem 2009 · PubMed 20161290
6. Abuawad A, Bozack AK et al. Nutrition, one-carbon metabolism and arsenic methylation. Toxicology 2021 · PubMed 33905762
7. Ponomarenko O, La Porte PF et al. Selenium-mediated arsenic excretion in mammals: a synchrotron-based study of whole-body distribution and tissue-specific chemistry. Metallomics 2017 · PubMed 29058732

Whole pathway: Arsen

Related pathways

• Quecksilber — Glutathion (GSH), Methionin

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