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Reactive metabolites

المؤلف:  Sue Jickells , Adam Negrusz (Editors)

المصدر:  Clarkes Analytical Forensic Toxicology

الجزء والصفحة:  p33-34

2026-09-15

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Reactive metabolites

Toxic metabolites can occur in the same way that pharmacologically active and/or inactive metabolites are produced. For example, deacetyl ation of phenacetin yields p-phenetidine, the precursor of substances believed to be responsible for methemoglobinemia. Similarly, paraoxon, the oxygenated metabolite of parathion, is responsible for the severe toxicity observed after the ingestion of parathion. Changes in the pathways of metabolism of a drug can also result in toxicity. In paracetamol intoxication (e.g. from drug overdose), the path ways responsible for sulfate and glucuronide conjugation become saturated and the concentrations of cysteine and mercapturic acid metabolites increase. When the production of these two metabolites increases sufficiently to deplete stores of glutathione, the active intermediate can no longer be conjugated and is thought to bind irreversibly to cellular macromolecules such as DNA, RNA and proteins, which results in a dose-related hepatic necrosis. It is believed that the toxic molecule arises from the oxidation of paracetamol to N-acetyl-p-benzoquinone mine (Fig. 1). Whatever the actual pathway, the admin istration of compounds that contain sulfhydryl groups has been shown to be effective in treatment of paracetamol intoxication, presumably because they are able to bind to the electrophilic species in the same way as glutathione does. Another example of drug toxicity induced by metabolism is that associated with acetylation. The rate of acetylation is controlled by an N-acetyltransferase that shows genetic polymorphism; about 60% of caucasians are classified as ‘slow’ acetylators. The extent of acetylation is related to the toxic effects of certain drugs. For example, the N-hydroxy metabolite of acetylated isoniazid is thought to cause isoniazid-related hepatotoxicity. This toxicity is more severe in ‘rapid’ acetylators than in ‘slow’ acetylators, but (as with paracetamol) some protection can be given by sulfhydryl compounds. There are diagnostic tests for acetylator status. In contrast, ‘slow’ acetylators appear to show a greater incidence of systemic lupus erythematosus after the administration of hydrazine drugs than do ‘rapid’ acetylators, as this toxic reaction is related to the parent drug.

The possible role of reactive metabolites should be taken into account in toxicological investigations.

Figure 1 Paracetamol metabolism.