Mechanisms, chemical structures and drug metabolism

From the studies that have been done by many laboratories over the last 2 decades, it is now clear that the toxicities produced by many drugs are due to their reactive metabolites. It is thought that, in many cases, reactive metabolites cause toxicity by binding covalently to tissue proteins. However, until recently it was difficult to identify these protein targets. Due to the development of an immunochemical approach, this problem has been overcome, as is illustrated here by studies that have been conducted on the metabolic basis of the idiosyncratic hepatitis caused by the inhalation anaesthetic halothane. The major problem to solve in the future will be to determine how protein adduct formation leads to toxicity. It is possible that protein adduct formation may alter an important cellular function or may lead to immunopathology, as is thought to occur in the case of halothane hepatitis. If an allergic reaction is suspected, purified protein targets of reactive metabolites can serve as antigens for identifying sensitized individuals. This information can be used to prevent not only an allergic reaction to the drug, but possibly cross-reactions to other drugs that are structurally related. Another important application of these studies is the design of safer alternative drugs that will not produce structurally similar toxic reactive metabolites.