Bioactivation and Tissue Toxicity

Bioactivation is a metabolic process that transforms less reactive substances into highly reactive metabolites, initiating tissue toxicity. This transformation can lead to various toxic effects, including carcinogenesis and teratogenesis. Reactive metabolites are classified into two main types: electrophiles and free radicals.

Electrophiles are electron-deficient species and are produced primarily by the enzyme cytochrome P-450 during the metabolism of compounds containing carbon, nitrogen, or sulfur. Significant electrophilic metabolites include epoxides, hydroxylamines, and nitroso derivatives. They can bond covalently to DNA and other nucleophilic components of cells, potentially causing mutations and cancer. The primary defense against electrophiles is their inactivation by sulfur-containing nucleophiles like glutathione.

Free radicals, on the other hand, are highly reactive molecules because of an unpaired electron. They are generated by similar enzymatic systems and can be either organic or inorganic, with some, like hydrogen peroxide and superoxide anion, being particularly damaging. They cause tissue toxicity through the peroxidation of cellular components. The body’s defense against free radical-induced toxicity includes using glutathione, membrane structure control, antioxidant scavengers such as vitamins A, E, and C, and enzymes that inactivate oxygen-derived free radicals. This intricate defense system underscores the body's capacity to manage the adverse effects of bioactivation.