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

This page shows the biochemical pathway of the substance Organophosphate: how it enters the body, which stations it passes and which steps it affects. Every statement has a source. The page describes general textbook knowledge and says nothing about any individual person.

In brief

Organophosphates are esters of phosphoric acid and are used as insecticides. In the liver they are converted into the oxon form, which binds to the active site of acetylcholinesterase. The enzyme can then no longer cleave acetylcholine, and the signal persists.

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. Organophosphate → Uptake Organophosphates enter the body via the skin, the airways and the gut. They dissolve in fat and pass through cell membranes. They thus reach the blood quickly. Source 1↑ supplies Because organophosphates dissolve in fat, skin, airways and gut bring them quickly into the blood and on into the tissues. established physiology Source 1
   ⚖ When the balance tips

   too much — If a lot is absorbed, more of it also spreads into adipose tissue, from which it is slowly released again.

   too little — If little is absorbed, little reaches the liver, and the amounts in the blood stay small.

   observed in studies · Source 1

2. Uptake → Conversion in the liver Enzymes of the cytochrome P450 family exchange the sulfur atom in the molecule for oxygen. CYP1A2, CYP2B6 and CYP3A4 are mainly involved. This forms the reactive oxon. Source 2, 4↑ supplies The CYP enzymes form the oxon from the thio compound, which binds to esterases; depending on the substance, the same enzymes also split part of it directly into inactive fragments. established physiology Source 2, 4
   ⚖ When the balance tips

   too much — If the CYP enzymes work quickly, a lot of oxon forms in a short time, and more of it reaches the blood.

   too little — If they work slowly, for example owing to differences in the CYP forms involved, less oxon forms, and more of the starting material remains.

   observed in studies · Source 2, 4

3. Conversion in the liver → Oxon form CYP enzymes · NADPH, oxygen This yields the oxon form. It binds to the active site of esterases far more strongly than the parent compound does. It mainly occupies acetylcholinesterase. Source 2, 1↓ depletes The oxon form occupies the active site of esterases, above all acetylcholinesterase, and switches them off; carboxylesterases bind part of it before it reaches the nerves. established physiology Source 2, 1
   ⚖ When the balance tips

   too much — If more oxon forms than PON1 and carboxylesterases can capture, a larger part of the acetylcholinesterase is occupied.

   too little — If little oxon forms, PON1 and the carboxylesterases largely capture it before it reaches acetylcholinesterase.

   established physiology · Source 1, 3

4. Oxon form → Cleavage by PON1 Paraoxonase 1 (PON1) is bound to HDL particles in the blood and cleaves the oxon form. Two calcium ions sit in its active site. Carboxylesterases also bind the oxon form. How fast depends partly on the form of the PON1 gene. Source 4, 5, 1↓ depletes PON1 cleaves the oxon form in the blood before it reaches acetylcholinesterase; how fast depends on the substance and on the form of the PON1 gene. established physiology Source 4, 5, 1
   ⚖ When the balance tips

   too much — If PON1 activity is high, more oxon is cleaved in the blood; in animal models acetylcholinesterase then remains less occupied.

   too little — If PON1 activity is low, for example owing to certain gene forms, the oxon stays in the blood longer; in animal models more acetylcholinesterase is then occupied.

   observed in studies · Source 4

5. Cleavage by PON1 → Dialkyl phosphates PON1 · calcium Cleavage yields dialkyl phosphates such as dimethyl and diethyl phosphate. They are water-soluble and leave the body with the urine. They no longer act on esterases. Source 6↓ depletes Dialkyl phosphates are the fragments with which the phosphate part leaves the body via the urine; they no longer act on esterases. established physiology Source 6
   ⚖ When the balance tips

   too much — If a lot of organophosphate is cleaved, dialkyl phosphates in the urine rise within hours to days.

   too little — If little is cleaved, only a few dialkyl phosphates appear in the urine; part of them may also come from residues in food that have already broken down.

   established physiology · Source 6

6. Acetylcholine → Choline + acetate acetylcholinesterase Acetylcholinesterase cleaves acetylcholine into choline and acetate. Choline is carried back into the nerve cell and joined into acetylcholine again there. This ends the signal. Source 3↑ supplies Cleavage ends the signal and returns choline, from which the nerve cell makes new acetylcholine. established physiology Source 3
   ⚖ When the balance tips

   too much — If a lot of choline forms because acetylcholine is cleaved rapidly, the nerve cell recovers it and makes new acetylcholine from it.

   too little — If little choline forms because acetylcholinesterase is occupied, the signal does not end, and the nerve cell gets less choline back.

   established physiology · Source 3

Further stations

• Organophosphate — ester of phosphoric acid Organophosphates are esters of phosphoric acid. As insecticides, mostly thio compounds are used that are altered in the body first. Only the liver turns them into the reactive form. Source 1↑ supplies The thio compound itself binds only weakly to esterases; it supplies the starting material from which the reactive oxon form arises in the liver. established physiology Source 1
  ⚖ When the balance tips

  too much — If more of the thio compound enters the body, more oxon form arises in the liver, and a larger part reaches acetylcholinesterase.

  too little — If little enters the body, the liver enzymes form little oxon, and PON1 and carboxylesterases largely capture it.

  established physiology · Source 1

• Oxon at the enzyme — binding to serine The oxon form binds to the serine in the active site of acetylcholinesterase. The enzyme can then no longer cleave acetylcholine, and the messenger stays in the synaptic cleft. The bond is released only very slowly. Source 3↓ depletes The oxon form attaches a phosphate group firmly to the serine of acetylcholinesterase; the bond is released only very slowly and can become permanent over time. established physiology Source 3
  ⚖ When the balance tips

  too much — If a large part of the acetylcholinesterase is occupied, acetylcholine stays in the synaptic cleft for a long time, and the signals to nerves, muscles and glands persist.

  too little — If only a small part is occupied, the free enzymes continue to cleave acetylcholine, and transmission stays brief.

  established physiology · Source 3

• Acetylcholine — messenger at the synapse Acetylcholine passes signals on to nerve, muscle and gland cells. After transmission it is cleaved in the synaptic cleft. Acetylcholinesterase determines how long it acts. Source 3↑ supplies Acetylcholine delivers the signal to nerve, muscle and gland cells; how long it acts is determined mainly by acetylcholinesterase, which cleaves it rapidly in the cleft. established physiology Source 3
  ⚖ When the balance tips

  too much — If acetylcholine builds up in the cleft, its receptors on muscles, nerves and glands stay constantly stimulated; muscles twitch, and glands release more secretion.

  too little — If little acetylcholine is present, its receptors are stimulated less often, and signals to muscles and glands are weaker.

  established physiology · Source 3

Cofactors in this pathway

• Calcium — Two calcium ions in the active site of paraoxonase 1, which cleaves the oxon form; without calcium, no cleavage Source 5
• HDL particles (PON1 carrier) — Carries PON1 in the blood: the enzyme is bound to HDL particles; this is where PON1 acts in the blood Source 4, 5In the ORY catalogue as a laboratory value: HDL-Cholesterin
• NADPH — Supplies the electrons for the cytochrome P450 reaction that forms the oxon form; without NADPH, no oxon form Source 2
• Glutathione — Cofactor of the glutathione S-transferases that break down some organophosphates; it is used up in the process Source 1In the ORY catalogue as a laboratory value: Glutathion (GSH)
• Choline — Building block of acetylcholine and cleavage product of acetylcholinesterase; it is carried back into the cell Source 3
• Oxygen — Is exchanged for the sulfur atom of the molecule during conversion in the liver Source 2

Sources

1. Costa LG. Current issues in organophosphate toxicology. Clin Chim Acta 2006 · PubMed 16337171
2. Buratti FM, Volpe MT et al. CYP-specific bioactivation of four organophosphorothioate pesticides by human liver microsomes. Toxicol Appl Pharmacol 2003 · PubMed 12620367
3. Colović MB, Krstić DZ et al. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol 2013 · PubMed 24179466
4. Furlong CE. Genetic variability in the cytochrome P450-paraoxonase 1 (PON1) pathway for detoxication of organophosphorus compounds. J Biochem Mol Toxicol 2007 · PubMed 17936934
5. Harel M, Aharoni A et al. Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat Struct Mol Biol 2004 · PubMed 15098021
6. Neves AP, Rosa ACS et al. Urinary dialkylphosphate metabolites in the assessment of exposure to organophosphate pesticides: from 2000 to 2022. Environ Monit Assess 2023 · PubMed 38049584

Related pathways

• DDT und DDE — conversion in the liver

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