reactive metabolite

A reactive metabolite is metabolism gone slightly wrong — instead of producing a tame, easily excreted product, an enzyme generates a chemically 'hot' molecule that is itching to react with whatever it bumps into. Like a spark thrown off a grinding wheel, it is short-lived but can do damage to nearby cellular machinery.

These metabolites are usually electrophilic species — for example quinones, epoxides, or reactive iminium ions — formed when phase I enzymes oxidize particular chemical groups. Being electron-poor, they form covalent bonds with electron-rich sites on proteins, DNA, or glutathione. Most are mopped up safely by glutathione, but those that escape can covalently modify cellular proteins.

Such covalent modification is implicated in idiosyncratic toxicities, notably some forms of drug-induced liver injury, and in immune-mediated reactions where a drug-modified protein is treated as foreign. Because reactive metabolites are hard to predict and rare to manifest clinically, medicinal chemists try to design out the chemical features (structural alerts) that tend to spawn them, and use trapping assays to detect them early.