Biotransformations Leading to Toxic Metabolites

As drugs are usually foreign chemicals, history of concern for the biotransformations of drugs leading to toxic metabolites formation is intrinsically linked to the history of xenobiotic metabolism studies. The biochemical conversions are usually of an enzymatic nature and yield reactive intermediates, which may be implicated in the toxicity as far as the final metabolites. Biotransformation begins with the transient formation of a reactive intermediate whose lifetime is long enough to allow an attack on cellular components. During the biotransformations affecting xenobiotics, five major kinds of chemical reactions may occur: oxidations, reductions, hydrolysis, substitutions, and eliminations. As Phase I and II reactions are part of this classification, each class of reactions can give rise to toxic metabolites. The formation of toxic metabolites and/or intermediates during the metabolism of drugs may occur by a considerable variety of pathways that are mediated by several enzyme systems. Formation of toxic metabolites is not the only pathway of biotransformation, and the overall metabolism is constituted toward detoxication and bioactivation processes. The toxic metabolites are themselves often further detoxified. The duality between a beneficial detoxication phenomenon (metabolism, drug resistance) and the occurrence of a toxic effect represents the cost for adaptability of metabolic enzymes to the diversity of xenobiotics.