MECHANISMS, CHEMICAL STRUCTURES AND DRUG-METABOLISM

From the studies that have been done by many laboratories over the las t 2 decades, it is now clear that the toxicities produced by many drug s are due to their reactive metabolites. It is thought that, in many c ases, reactive metabolites cause toxicity by binding covalently to tis sue proteins, However, until recently it was difficult to identify the se protein targrts. Due to the development of an immunochemical approa ch, this problem has been overcome, as is illustrated here by studies that have been conducted on the metabolic basis of the idiosyncratic h epatitis caused by the inhalation anaesthetic halothane. The major pro blem to solve in the future will be to determine how protein adduct fo rmation leads to toxicity. It is possible that protein adduct formatio n may alter an important cellular function or may lead to immunopathol ogy, as is thought to occur in the case of halothane hepatitis. If an allergic reaction is suspected, purified protein targets or reactive m etabolites can sct?ie as antigens for identifying sensitized individua ls, This information can be used to prevent not only an allergic react ion to the drug, but possibly cross-reactions to other drugs that are structurally related. Another important application of these studies i s the design of safer alternative drugs that will not produce structur ally similar toxic reactive metabolites.