17.11: 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.

Bioactivation is an enzyme-mediated process that converts inert substances into highly reactive metabolites, such as electrophiles and free radicals. These bioactive metabolites interact with tissues, causing various adverse effects, including hepatotoxicity and nephrotoxicity.

Electrophiles, such as epoxides, hydroxylamines, and nitroso derivatives, are electron pair-deficient species. They are generated during cytochrome P450-mediated metabolism, typically as reactive intermediates, during xenobiotic processing.

Typically, these electrophiles are inactivated by glutathione conjugation. But, when in excess, they can bind covalently to nucleophilic macromolecules like DNA, leading to mutations and cancer.

Free radicals have unpaired electrons as cations, anions, or neutral species. The NADPH-cytochrome P450 system or reductases typically form free radicals during metabolic reactions.

Inorganic free radicals like hydroxyl radical and superoxide anion can cause extensive tissue damage, leading to mutation or cancer.