Reactive electrophilic metabolite (REM)

Reactive electrophilic metabolites (REMs) are chemically unstable, electron-deficient intermediates generated during the metabolic biotransformation of xenobiotics, primarily by Cytochrome P450 enzymes (Guengerich, 2008, Chem Res Toxicol). These species are highly prone to reacting with nucleophilic centers on cellular macromolecules, such as the sulfhydryl groups in proteins or nitrogenous bases in DNA, leading to the formation of stable covalent adducts (Liebler, 2008, Chem Res Toxicol). This process, known as bioactivation, is a central mechanism in toxicology, as it can result in protein dysfunction, oxidative stress, and the initiation of mutagenic or carcinogenic pathways (Park et al., 2005, Nat Rev Drug Discov). A classic example is the formation of N-acetyl-p-benzoquinone imine (NAPQI) from acetaminophen, which causes severe hepatotoxicity when endogenous glutathione stores are depleted (Hinson et al., 2010, Handb Exp Pharmacol). While REMs are not therapeutic targets themselves, they represent significant safety liabilities in drug development. Pharmacological intervention typically focuses on scavenging these metabolites using nucleophilic agents like N-acetylcysteine or Mesna to prevent cellular damage (Flanagan & Meredith, 1991, Am J Med).

Other names

Reactive intermediateElectrophilic speciesBioactivated metaboliteToxic metabolite

Covalent binding to cellular nucleophiles and depletion of endogenous antioxidants like glutathione