Bioactivation and Tissue Toxicity

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.