SELECTIVE PROTEIN COVALENT BINDING AND TARGET ORGAN TOXICITY

Protein covalent binding by xenobiotic metabolites has long been assoc iated with target organ toxicity but mechanistic involvement of such b inding has not been widely demonstrated, Modern biochemical, molecular , and immunochemical approaches have facilitated identification of spe cific protein targets of xenobiotic covalent binding, Such studies hav e revealed that protein covalent binding is not random, but rather sel ective with respect to the proteins targeted. Selective binding to spe cific cellular target proteins may better correlate with toxicity than total protein covalent binding. Current research is directed at chara cterizing and identifying the targeted proteins and clarifying the eff ect of such binding on their structure, function, and potential roles in target organ toxicity. The approaches employed to detect and identi fy the targeted proteins are described, Metabolites of acetaminophen, halothane, and 2,5-hexanedione form covalently bound adducts to recent ly identified protein targets. The selective binding may influence hom eostatic or other cellular responses which in turn contribute to drug toxicity, hypersensitivity, or autoimmunity. (C) 1997 Academic Press.