Paracetamol metabolic intermediates

Figure 7.19 Proposed metabolic activation of paracetamol to a toxic, reactive intermediate /V-acetyl-p-benzoquinone imine (NAPQI). This can react with glutathione (GSH) to form a conjugate or with tissue proteins. Alternatively, NAPQI can be reduced back to paracetamol by glutathione, forming oxidized glutathione (GSSG).

Paracetamol, adriamycin, quinones, nitrosamines, aromatic amines, halothane etc. form free-radical intermediates by metabolic activation in the liver.)... 

Biotransformation, especially phase I metabolic reactions, cannot be assumed to be synonymous with detoxification because some drugs (although a minority) and xenobiotics are converted to potentially toxic metabolites (e.g. parathion, fluorine-containing volatile anaesthetics) or chemically reactive intermediates that produce toxicity (e.g. paracetamol in cats). The term lethal synthesis refers to the biochemical process whereby a non-toxic substance is metabolically converted to a toxic form. The poisonous plant Dichapetalum cymosum contains monofluoroacetate which, following gastrointestinal absorption, enters the tricarboxylic acid (Krebs) cycle in which it becomes converted to monofluorocitrate. The latter compound causes toxicity in animals due to irreversible inhibition of the enzyme aconitase. The selective toxicity of flucytosine for susceptible yeasts (Cryptococcus neoformans, Candida spp.) is attributable to its conversion (deamination) to 5-fluorouracil, which is incorporated into messenger RNA. 

Since the pioneering work of the Millers (1) and Magee and Barnes (2), it has become increasingly evident that many stable chemicals are metabolized to electrophilic intermediates that alkylate and arylate tissue macromolecules. This laboratory (3 -5) has shown that drugs, such as acetaminophen (paracetamol), phenacetin, furosemide (frusemide), isoniazid, and iproniazid, also are oxidatively activated by microsomal enzymes to electrophilic intermediates that covalently bind to tissue macromolecules and cause massive tissue necrosis. 

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