General pathology · Cell injury, adaptation and death
Chemical (toxic) cell injury: direct and after metabolism !
- Mechanism
Some toxins harm cells directly; others are harmless until the liver converts them into reactive molecules.
Updated 2026-11-01
What it is
Chemicals injure cells in two ways. Some act directly, by binding to a vital molecule or organelle (mercury, cyanide, many cancer drugs). Others must first be activated, usually by cytochrome P450 enzymes in the liver, into reactive metabolites or free radicals that attack membranes and proteins. This explains why the liver is the classic target and why enzyme inducers such as alcohol increase the risk.
Step by step
- The drug or chemical enters the hepatocyte.
- Most is detoxified by conjugation (glucuronidation, sulfation) and excreted.
- A fraction is oxidized by cytochrome P450 (CYP2E1, CYP3A4) into a reactive metabolite.
- Glutathione binds the reactive metabolite and neutralizes it.
- In overdose glutathione runs out; the metabolite binds proteins and causes oxidative stress.
- Mitochondria fail, the cell dies (mainly necrosis) in zone 3, and transaminases rise.
Examples of chemical cell injury
| Agent | Activation | Main target and lesion |
|---|---|---|
| Acetaminophen (paracetamol) | P450 to NAPQI | Liver, centrilobular necrosis |
| Carbon tetrachloride | P450 to a free radical | Liver, fatty change and necrosis |
| Mercury salts | Direct (sulfhydryl binding) | Kidney tubules, gut, nervous system |
| Cyanide | Direct (complex IV) | All tissues; brain and heart first |
| Amatoxin (Amanita mushrooms) | Direct (RNA polymerase II) | Liver and kidney necrosis |
| Methanol | Alcohol dehydrogenase to formic acid | Retina and optic nerve, metabolic acidosis |
Clinical notes
- Acetaminophen is the leading cause of drug-induced acute liver failure in many countries; early acetylcysteine prevents most of the damage.
- Fomepizole blocks alcohol dehydrogenase so methanol and ethylene glycol are not converted to their toxic acids.
Test yourself
Think of the answer, then tap the question to see it.
Why does acetaminophen damage zone 3 of the liver lobule?
Zone 3 (centrilobular) hepatocytes have the most CYP2E1, which makes the toxic metabolite NAPQI, and the least oxygen.
How does chronic alcohol use increase acetaminophen toxicity?
It induces CYP2E1, producing more NAPQI, and lowers glutathione stores that would neutralize it.
Which chemical injures cells directly, without metabolic activation?
Mercury chloride, which binds sulfhydryl groups of membrane proteins; or cyanide, which blocks cytochrome c oxidase.
Related
- Causes of cell injury
- Oxidative stress and free-radical injury
- Fatty change (steatosis)
- Injury by therapeutic drugs: the classic examples
- Heavy metals: lead, mercury, arsenic and cadmium
- Alcohol: how it injures the liver, brain, heart and fetus
Related conditions
- Acetaminophen toxicity
- Drug-induced liver injury
- Acute liver failure
- Mushroom poisoning (Amanita)
- Mercury poisoning
- Paraquat poisoning
- Methanol poisoning
- Ethylene glycol poisoning
- Cyanide poisoning
- Alcoholic liver disease (biochemistry)
Elsewhere in DurgiPedia
- Acetaminophen metabolism and NAPQI
- Cytochrome P450 system
- NAPQI (N-acetyl-p-benzoquinone imine)
- N-acetylcysteine (NAC)
- Cytochrome P450 2E1 (CYP2E1, MEOS)
- α-Amanitin
- Xenobiotic biotransformation: phases I, II and III
- Glutathione (GSH)
In Pharmacology
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Acetaminophen overdose: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2024); Acetaminophen: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2024); Mercury (World Health Organization, 2024).
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Representative model, for educational purposes only.