reactive metabolite

A reactive metabolite is metabolism's dangerous byproduct. While trying to make a drug easier to excrete, the body sometimes generates a chemically aggressive intermediate — an electron-hungry molecule that, instead of leaving quietly, latches onto and damages cellular proteins, DNA, or membranes.

These intermediates often arise during phase I oxidation by cytochrome P450, which can create electrophiles or free radicals. Normally protective systems, especially conjugation with glutathione, neutralize them harmlessly. Toxicity occurs when reactive metabolites are produced faster than they can be detoxified, or when protective stores are depleted.

The classic example is paracetamol (acetaminophen): in overdose its reactive metabolite NAPQI overwhelms the liver's glutathione supply and binds to liver proteins, causing hepatotoxicity — which is why the antidote N-acetylcysteine works by replenishing glutathione. Reactive metabolites are also implicated in some idiosyncratic, hard-to-predict drug toxicities and hypersensitivity reactions.